Inhibitors of tyrosine kinases and uses thereof

ABSTRACT

Disclosed herein are compounds that inhibit the activity of particular tyrosine kinases. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of tyrosine kinase-mediated diseases or conditions or tyrosine kinase-dependent diseases or conditions are provided.

RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.60/758,617 entitled “INHIBITORS OF TYROSINE KINASES” filed Jan. 13,2006, which is herein incorporated by reference.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds and compositions to inhibit theactivity of tyrosine kinases.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family ofnon-receptor tyrosine kinases, is a key signaling enzyme expressed inall hematopoietic cells types except T lymphocytes and natural killercells. Btk plays an essential role in the B-cell signaling pathwaylinking cell surface B-cell receptor (BCR) stimulation to downstreamintracellular responses.

Btk is a key regulator of B-cell development, activation, signaling, andsurvival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer andSchwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a rolein a number of other hematopoetic cell signaling pathways, e.g., Tolllike receptor (TLR) and cytokine receptor-mediated TNF-α production inmacrophages, IgE receptor (FcepsilonRI) signaling in Mast cells,inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells,and collagen-stimulated platelet aggregation. See, e.g., C. A. Jeffries,et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J.Horwood, et al., (2003), The Journal of Experimental Medicine197:1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry280(48):40261-40270; Vassilev et al. (1999), Journal of BiologicalChemistry 274(3):1646-1656, and Quek et al. (1998), Current Biology8(20):1137-1140.

SUMMARY OF THE INVENTION

Compounds, compositions and methods for inhibiting the activity of asubset of tyrosine kinases (such as Btk) are provided. In oneembodiment, compounds provided herein are used to inhibit Bruton'styrosine kinase (Btk), and are thus inhibitors of Btk. Processes for thepreparation of compounds that inhibit the activity of certain tyrosinekinases, compositions that include the compounds, as well as methods ofuse thereof are provided.

Compounds provided herein include those that have a structure of Formula(Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula(IIIa), Formula (Mb), Formula (IIIc), Formula (IV), Formula (V), and/orFormula (VI), and pharmaceutically acceptable salts, solvates, esters,acids and prodrugs thereof. In certain embodiments, isomers andchemically protected forms of compounds having a structure representedby Formula (Ia), Formula (Ib), Formula (Ic), Formula (II), Formula(III), Formula (IIIa), Formula (Mb), Formula (IIIc), Formula (IV),Formula (V), and/or Formula (VI), are also provided.

In one aspect, provided herein are compounds of Formula (III):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or        1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;    -   L is —X^(250a)—Y²⁵⁰— or —Y²⁵⁰—X^(250a)—, wherein,        -   X^(250a) is a substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—, —C(═O)—, —NR⁴⁵—,            —NH—, —NHC(═O)—, —NR⁴⁵C(═O)—, —NR⁴⁵C(═O)NR⁴⁵—, —C(═O)NH—,            —C(═O)NR⁴⁵—, —OC(═O)—, —C(═O)O—, —NHSO₂—, —NR⁴⁵SO₂—,            —SO₂NH—, —SO₂NR⁴⁵—, —C(R⁴⁵)═NO—, —CH═NO—, —ON═CH—,            heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR⁴⁵C(═O)O—, or            —OC(═O)NR⁴⁵—;        -   where each R⁴⁵ is independently selected from among            hydrogen, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₃-C₈cycloalkyl, substituted or            unsubstituted C₂-C₆alkenyl, substituted or unsubstituted            C₂-C₆alkynyl;    -   M is N or CH;    -   W is

-   -   -   E is oxygen or sulfur;

    -   R¹⁰⁰ is halogen, —OH, or an optionally substituted group        selected from among C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        phenyl, C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl,        C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl,        C₁-C₄alkyl(C₂-C₈heterocycloalkyl), heteroaryl,        C₁-C₄alkyl(heteroaryl), C₁-C₆alkoxy, C₁-C₆alkenyloxy,        C₁-C₆alkynyloxy, or —NR^(102a)R^(102b);        -   R^(102a) and R^(102b) are independently hydrogen, or an            optionally substituted group selected from among C₁-C₆alkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, aryl, aralkyl, heteroaryl,            hetero aralkyl, C₃-C₈cycloalkyl,            C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl, and            C₁-C₄alkyl(C₂-C₈heterocycloalkyl);        -   R²⁰⁰ is an optionally substituted group selected from among            C₂-C₁₀acyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,            C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl, hetero            aralkyl, C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl,            aminosulfonyl, C₁-C₆alkylaminosulfonyl,            di(C₁-C₆alkyl)aminosulfonyl, and C₁-C₆alkylsulfonylamino;

    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl;

    -   n is 0, 1, or 2; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example, in someembodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene.In other embodiments, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene.

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In other embodiment, Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—, —C(═O)—,—NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO₂—,—SO₂NH—, —NHC(═O)O—, or —OC(═O)NH—; E is O; and R^(350a) is hydrogen, asubstituted or unsubstituted C₁-C₆alkyl, or a substituted orunsubstituted C₁-C₆haloalkyl.

In some embodiments, R^(350a) is hydrogen or a substituted orunsubstituted C₁-C₆alkyl. In yet other embodiments, R^(350a) is hydrogenor a C₁-C₆alkyl. In yet other embodiments, R^(350a) is hydrogen.

In some other embodiments, X^(250a) is a substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆haloalkyl, substituted orunsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, orsubstituted or unsubstituted C₂-C₆haloalkynyl; and n is 1. In otherembodiments, X^(250a) is a substituted or unsubstituted C₁-C₆alkyl, or asubstituted or unsubstituted C₂-C₆alkenyl.

In some embodiments, compounds provided herein have a structure selectedfrom among:

In certain embodiments, R¹⁰⁰ is halogen, or an optionally substitutedgroup selected from among C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,phenyl, C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl,C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl,C₁-C₄alkyl(C₂-C₈heterocycloalkyl), heteroaryl, andC₁-C₄alkyl(heteroaryl); R²⁰⁰ is an optionally substituted group selectedfrom among C₂-C₁₀acyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl, hetero aralkyl,C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl, aminosulfonyl,C₁-C₆alkylaminosulfonyl, and di(C₁-C₆alkyl)aminosulfonyl.

In some embodiments, R^(350a) is hydrogen; Y²⁵⁰ is a bond, —C(═O)—,—NHC(═O)—, —C(═O)NH—.

In other embodiments, L is selected from among:

C₁-C₄ alkyl,

In yet other embodiments, L is selected from among:

C₁-C₄ alkyl,

In one embodiment, compounds provided herein have a structure of Formula(IIIc). In other embodiments, compounds provided herein have a structureof Formula (IIIa). In yet other embodiments, compounds provided hereinhave a structure of Formula (IIIb).

In some embodiments, L is C₁-C₄ alkyl or

and R²⁰⁰ is an optionally substituted group selected from amongC₂-C₁₀acyl, aryl, heteroaryl, heteroaralkyl, C₁-C₆alkylsulfonyl,C₂-C₆alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In other embodiments, R²⁰⁰ is an optionally substituted group selectedfrom among C₂-C₁₀acyl, aryl, heteroaryl, heteroaralkyl,C₁-C₆alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In one aspect, L is selected from among C₁-C₄ alkyl,

R¹⁰⁰ is an optionally substituted group selected from among C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl, C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl,C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl,C₁-C₄alkyl(C₂-C₅heterocycloalkyl), heteroaryl, andC₁-C₄alkyl(heteroaryl); R²⁰⁰ is an optionally substituted group selectedfrom among C₂-C₁₀acyl, aryl, heteroaryl, hetero aralkyl,C₁-C₆alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In some embodiments, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylenesubstituted at the 2 position with

and substituted at the 6 position with

In yet other embodiments, Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—,—C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—,—NHSO₂—, —SO₂NH—, —NHC(═O)O—, or —OC(═O)NH—; E is O; and R^(350a) ishydrogen, or a substituted or unsubstituted C₁-C₆alkyl.

In certain embodiments, X^(250a) is a substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆haloalkyl, substituted orunsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, orsubstituted or unsubstituted C₂-C₆haloalkynyl; and n is 1.

In some embodiments, R¹⁰⁰ is halogen, or an optionally substituted groupselected from among C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl,C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl, C₁-C₄alkyl(C₃-C₈cycloalkyl),C₂-C₈heterocycloalkyl, C₁-C₄alkyl(C₂-C₈heterocycloalkyl), heteroaryl,and C₁-C₄alkyl(heteroaryl); R²⁰⁰ is an optionally substituted groupselected from among C₂-C₁₀acyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl, heteroaralkyl, C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl, aminosulfonyl,C₁-C₆alkylaminosulfonyl, and di(C₁-C₆alkyl)aminosulfonyl.

In other embodiments, R^(350a) is hydrogen; Y²⁵⁰ is —C(═O)—; andX^(250a) is a substituted or unsubstituted C₁-C₆alkyl.

In certain embodiments, L is

In some embodiments, compounds provided herein have a structure ofFormula (Mb). In other embodiments compounds provided herein have astructure of Formula (IIIa). In yet other embodiments, compoundsprovided herein have a structure of Formula (IIIc).

In another embodiment, provided herein are compounds of Formula (IV):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene;    -   R^(d) is —OH, or —NH—C(O)—R^(e);    -   R^(c) is H or C₁-C₄alkyl, halogen, or C₁-C₄haloalkyl;    -   R^(e) is a substituted or unsubstituted group selected from        among C₁-C₆ alkyl, aryl, or heteroaryl; and    -   pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,substituted at the 2 position with

and substituted at the 7 position with

In certain embodiments, R^(c) is H; and R^(e) is a substituted orunsubstituted group selected from among aryl, and heteroaryl. In yetother embodiments, R^(e) is a substituted or unsubstituted groupselected from among phenyl, and heteroaryl containing 1 or 2 N atoms.

In another embodiment, provided herein are compounds of Formula (V):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]        isoquinolin-2,6-ylene;    -   L is —X^(250a)—Y²⁵⁰—X^(250b)— or —X^(250b)—Y²⁵⁰—X^(250a)—,        wherein,        -   X^(250a) is a bond, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—, —C(═O)—, —NR⁴⁵—,            —NH—, —NHC(═O)—, —NR⁴⁵C(═O)—, —NR⁴⁵C(═O)NR⁴⁵—, —C(═O)NH—,            —C(═O)NR⁴⁵—, —OC(═O)—, —C(═O)O—, —NHSO₂—, —NR⁴⁵SO₂—,            —SO₂NH—, —SO₂NR⁴⁵—, —C(R⁴⁵)═NO—, —CH═NO—, —ON═CH—,            heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR⁴⁵C(═O)O—, or            —OC(═O)NR⁴⁵—;        -   X^(250b) is a bond, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   where each R⁴⁵ is independently selected from among            hydrogen, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₃-C₈cycloalkyl, substituted or            unsubstituted C₂-C₆alkenyl, substituted or unsubstituted            C₂-C₆alkynyl;    -   R^(e) is a substituted or unsubstituted group selected from        among C₁-C₆ alkyl, aryl, or heteroaryl;    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In certain embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In other embodiments, Y²⁵⁰ is a bond; and R^(350a) is hydrogen, asubstituted or unsubstituted C₁-C₆alkyl, a substituted or unsubstitutedC₁-C₆haloalkyl.

In one aspect, X^(250a) is a bond; and X^(250b) is a bond.

In another aspect, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 6 position with

In some embodiments, X^(250a) is a bond, substituted or unsubstitutedC₁-C₆alkyl; Y²⁵⁰ is a bond, —O—, —C(═O)—, —NH—, —NHC(═O)—, —NR⁴⁵C(═O)—,—NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHC(═O)O—, or —OC(═O)NH—;and X²⁵⁰¹³ is a bond, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆haloalkyl.

In some embodiments, R^(350a) is hydrogen, a substituted orunsubstituted C₁-C₆alkyl, a substituted or unsubstituted C₁-C₆haloalkyl.In some embodiments, R^(350a) is hydrogen.

In other embodiments, Y²⁵⁰ is a bond, —NHC(═O)—, —C(═O)NH—, —OC(═O)—, or—C(═O)O—.

In another aspect, provided herein are compounds of Formula (VI):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or        1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;    -   L is a substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆haloalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,        substituted or unsubstituted C₅-C₈cycloalkenyl, substituted or        unsubstituted C₂-C₆alkenyl, substituted or unsubstituted        C₂-C₆heteroalkenyl, substituted or unsubstituted        C₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, or        substituted or unsubstituted C₂-C₆haloalkynyl;    -   R^(f) is a substituted or unsubstituted C₂-C₆alkynyl;    -   R^(g) is H, or an optionally substituted group selected from        among C₂-C₁₀acyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₃-C₆cycloalkyl, C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl,        hetero aralkyl, C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl,        aminosulfonyl, C₁-C₆alkylaminosulfonyl, and        di(C₁-C₆alkyl)aminosulfonyl;    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In some embodiments, L is a substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆haloalkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₂-C₆alkenyl, or substituted or unsubstituted C₂-C₆heteroalkenyl; andR^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl. Inother embodiments, L is a substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₂-C₆alkenyl, or substituted or unsubstitutedC₂-C₆heteroalkenyl.

In other embodiments, R^(g) is H, or an optionally substituted groupselected from among C₂-C₁₀acyl, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, or C₁-C₁₀alkoxycarbonyl.

In some embodiments, L is a substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₂-C₆alkenyl; and R^(g) is H, or anoptionally substituted C₁-C₆alkyl.

In some embodiments, L is selected from among a substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆haloalkyl,substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, orsubstituted or unsubstituted C₂-C₆haloalkynyl,

In other embodiments, L is selected from among a substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,

In yet other embodiments, L is selected from among a substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In one aspect, provided herein is a compound selected from among:2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 1);2-(2,6-dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 2);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 3);2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 4);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 5);2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 6);2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-{2-[(4-oxo-4-phenyl-4λ^(5[)1,4]azaphosphinan-1-yl)-carbonyl]ethenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 7);2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 8);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 9);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-fluorophenyl)-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 10);2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-methoxyphenyl)-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 11);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 12);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 13);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 14);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-methyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 15);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-trans-phenyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 16);2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-cis-phenyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 17);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 18);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 19);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-chlorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 20);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 21);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 22);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-4-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 23);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 24);2-(3-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 25);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-2-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 26);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyrimidin-2-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 27);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(2,6-dichlorophenylmethyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 28);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 29);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-fluorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 30);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-tert-butyloxycarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 31);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N—(N,N-dimethylaminosulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 32);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-ethylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 33);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(isopropylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 34);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(ethylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 35);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-isopropylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 36);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2-(phenylsulfonyl)-ethenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 37);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-prop-2-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 38);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-2,2-difluorobutynyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 39);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2,2-difluoro-1-hydroxy-2-(N-phenylmethyl-[1,2,3]triazol-4-yl)-ethyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 40);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-(1-hydroxy-3-phenylprop-2-yn-1-yl)-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 41);2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (Compound 42);2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 43);2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehydeoxime (Compound 44); benzoic acid[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide(Compound 45); 4-(N,N-dimethylamino)-benzoic acid[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide(Compound 46); pyridine-2-carboxylic acid[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide (Compound 47);pyridine-3-carboxylic acid[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide(Compound 48); 2-methoxy-benzoic acid[2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide(Compound 49);2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{2-[4-(4-fluorophenyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 50); and(S)-2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{N-[1-(phenylsulfonyl)hex-1-en-3-yl]-amino-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 51).

In a further aspect are provided pharmaceutical compositions, whichinclude a therapeutically effective amount of at least one of any of thecompounds herein, or a pharmaceutically acceptable salt,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate. In certain embodiments,compositions provided herein further include a pharmaceuticallyacceptable diluent, excipient and/or binder.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically effectivederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases,disorders or conditions that are modulated or otherwise affected bytyrosine kinase activity, or in which tyrosine kinase activity isimplicated, are provided. The effective amounts and concentrations areeffective for ameliorating any of the symptoms of any of the diseases,disorders or conditions disclosed herein.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

In another aspect, provided herein is a method for inhibiting Bruton'styrosine kinase or a homolog thereof in a subject in need thereof byadministering to the subject a composition containing a therapeuticallyeffective amount of any of the above-mentioned compounds.

Articles of manufacture containing packaging material, a compound orcomposition or pharmaceutically acceptable derivative thereof providedherein, which is effective for inhibiting the activity of certaintyrosine kinase(s), such as Btk, within the packaging material, and alabel that indicates that the compound or composition, orpharmaceutically acceptable salt, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for inhibiting the activity of tyrosinekinase(s), such as Btk, are provided.

In a further aspect, provided herein is a method for inhibiting Bruton'styrosine kinase in a subject in need thereof by administering to thesubject thereof a composition containing a therapeutically effectiveamount of at least one reversible inhibitor of Btk, including any of theabove-mentioned compounds, which are described herein. In someembodiments, the subject in need is suffering from an autoimmunedisease, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia.

In other embodiments, the subject in need is suffering from aheteroimmune condition or disease, e.g., graft versus host disease,transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In certain embodiments, the subject in need is suffering from aninflammatory disease, e.g., asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In further embodiments, the subject in need is suffering from a cancer.In one embodiment, the cancer is a B-cell proliferative disorder, e.g.,diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds. In one embodiment, the anti-cancer agent is an inhibitor ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; PKC-beta inhibitors; PI3Kinhibitors; mTOR inhibitors; or an antibody effective for treatingcancer (e.g., rituxan).

In further embodiments, the subject in need is suffering from athromboembolic disorder, e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, or deep venous thrombosis.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone reversible inhibitor of Btk, including any of the above-mentionedcompounds. In one embodiment, the autoimmune disease is arthritis. Inanother embodiment, the autoimmune disease is lupus. In someembodiments, the autoimmune disease is rheumatoid arthritis, psoriaticarthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus,diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis,Graves' disease Sjögren's syndrome, multiple sclerosis, Guillain-Barrésyndrome, acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount ofat least one reversible inhibitor of Btk, including any of theabove-mentioned compounds. In some embodiments, the heteroimmuneconditioin or disease is graft versus host disease, transplantation,transfusion, anaphylaxis, allergy, type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, or atopic dermatitis.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone reversible inhibitor of Btk, including any of the above-mentionedcompounds. In some embodiments, the inflammatory disease is asthma,inflammatory bowel disease (including Crohn's disease and ulcerativecolitis), appendicitis, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In yet another aspect, provided herein is a method for treating a cancerby administering to a subject in need thereof a composition containing atherapeutically effective amount of at least one reversible inhibitor ofBtk, including any of the above-mentioned compounds. In one embodiment,the cancer is a B-cell proliferative disorder, e.g., diffuse large Bcell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma,chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds. In one embodiment, the anti-cancer agent is an inhibitor ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone reversible inhibitor of Btk, including any of the above-mentionedcompounds. In some embodiments, the thromboembolic disorder ismyocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, or deepvenous thrombosis.

Any of the combinations of the groups described above for the variousvariables is contemplated herein.

The terms “inhibits, inhibiting, or inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. All references cited herein, including patents,patent applications, and publications, are hereby incorporated byreference in their entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The appended claims particularly point out features set forth herein. Abetter understanding of the features and advantages of the presentdisclosure will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples described herein are utilized.

Disclosed herein are compounds that inhibit the activity the activity ofa subset of tyrosine kinase(s), compositions that include the compounds,and methods of their use. Compounds disclosed herein are inhibitors ofcertain tyrosine kinase(s) (e.g., Btk), and are useful in the treatmentof diseases, disorders, or conditions that would benefit from theinhibition of these tyrosine kinase(s). In some embodiments, compoundsprovided herein are used to inhibit the activity of Bruton's tyrosinekinase (Btk).

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_(—)000052).

The term “Bruton's tyrosine kinase homolog,” as used herein, refers toorthologs of Bruton's tyrosine kinase, e.g., the orthologs from mouse(GenBank Acession No. AAB47246), dog (GenBank Acession No.XP_(—)549139.), rat (GenBank Acession No. NP_(—)001007799), chicken(GenBank Acession No. NP_(—)989564), or zebra fish (GenBank Acession No.XP_(—)698117), and fusion proteins of any of the foregoing that exhibitkinase activity towards one or more substrates of Bruton's tyrosinekinase (e.g. a peptide substrate having the amino acid sequence“AVLESEEELYSSARQ”).

Btk is involved in abnormal levels of cell proliferation, apoptosis,cell migration and invasion, and angiogenesis associated with tumorgrowth. Btk is a key regulator of B-cell development, activation,signaling, and survival. In addition, Btk plays a role incollagen-stimulated platelet aggregation. Btk's function as both aregulator of apoptosis and its involvement in a number of developmentalprocesses makes Btk a desirable target for anti-cancer agents,anti-inflammatory agents, and anti-viral agents, anti-thromboembolicagents, as well as for treating autoimmune disease and acuteinflammatory reactions.

Btk may have a role in infectious and noninfectious inflammatory eventsand autoimmune and other inflammatory diseases. These autoimmune andinflammatory diseases, disorders, and syndromes include inflammatorypelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis,encephalitis, meningitis, myocarditis, nephritis, osteomyelitis,myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis,appendictitis, pancreatitis, cholocystitus, agammaglobulinemia—an immunedeficiency disease characterized by defects in B cell maturation andfunction, psoriasis, allergy, Crohn's disease, irrtiable bowel syndrome,ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's diesease, Parkinson's disease, Alzheimer's disease, Type Idiabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoidarthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis,chronic idiopathic thrombocytopenic purpura, Waldenströmmacroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopicdermatitis, degenerative joint disease, vitiligo, autoimmunehypopituatarism, Guillain-Barre syndrome, Behcet's disease,scleracierma, mycosis fungoides, acute inflammatory responses (such asacute respiratory distress syndrome and ischemia/reperfusion injury),and Graves disease.

Btk-associated lymphomas and include B-cell lymphoma, Hodgkin's andnon-Hodgkin's lymphoma, hairy cell leukemia, chronic and acutemylelogenous leukemia, multiple myeloma, EBV lymphomia, acutelymphoblastic leukemia, and chronic lymphocytic leukemia.

Accordingly, while not being bound by theory, it is believed thatinhibiting the activity of Btk is useful for treating any of thefollowing conditions.

In some embodiments, the methods described herein can be used to treatan autoimmune disease, which includes, but is not limited to, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, the methods described herein can be used to treatheteroimmune conditions or diseases, which include, but are not limitedto graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis.

In further embodiments, the methods described herein can be used totreat an inflammatory disease, which includes, but is not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In yet other embodiments, the methods described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenströmmacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In further embodiments, the methods described herein can be used totreat thromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine©,” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of the compounds described herein fortreating any of the foregoing diseases.

For example, dosing of the compounds for treating an autoimmune diseasecan be assessed in a mouse model of rheumatoid arthitis. In this model,arthritis is induced in Balb/c mice by administering anti-collagenantibodies and lipopolysaccharide. See Nandakumar et al. (2003), Am. J.Pathol 163:1827-1837., L. Svensson, R. Holmdahl, Am. J. Pathol. 2003,163, 1827).

In another example, dosing of the compounds for the treatment of B-cellproliferative disorders can be examined in, e.g., a human-to-mousexenograft model in which human B-cell lymphoma cells (e.g. Ramos cells)are implanted into immunodefficient mice (e.g., “nude” mice) asdescribed in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

While not wishing to be bound to theory, phosphatases can also play arole in a “disease, disorder, or syndrome responsive to the inhibitionof tyrosine kinases” as cognates of tyrosine kinases; that is, tyrosinekinases phosphorylate and phosphatases dephosphorylate, for example,protein substrates. Therefore, compounds of the invention, whilemodulating tyrosine kinase activity as described herein, may alsomodulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. As previously stated, thecompounds of the invention are useful for treating diseasescharacterized in part by abnormal levels of cell proliferation (i.e.tumor growth), progrmamed cell death (apoptosis), cell migration andinvasion, and angiogenesis associated with tumor growth.

The therapeutic efficacy of the compound for treating any of theforegoing diseases can be optimized during a course of treatment. Forexample, a subject being treated can undergo a diagnostic evaluation tocorrelate the relief of disease symptoms or pathologies to inhibition ofthe relevant tyrosine kinase in vivo by administering a given dose ofany of the compounds described herein. Cellular assays for determiningin vivo tyrosine kinase are available. For example, since activated Btkis phosphorylated at tyrosine 223 (Y223) and tyrosine 551 (Y551),phospho-specific immunocytochemical staining of P-Y223 orP-Y551-positive cells can be used to detect or quantify activation ofBkt in a population of cells (e.g., by FACS analysis of stained vsunstained cells). See, e.g., Nisitani et al. (1999), Proc. Natl. Acad.Sci, USA 96:2221-2226. Thus, the amount of the compound that isadministered to a subject can be increased or decreased as needed so asto maintain a level of inhibition of the target tyrosine kinase (e.g.,Btk) optimal for treating the subject's disease state.

Generally, the compounds used in the methods described herein areidentified or characterized in an in vitro assay, e.g., an acellularbiochemical assay or a cellular functional assay. Such assays are usefulto determine an in vitro IC₅₀ for a compound.

For example, an acellular kinase assay can be used to determine, e.g.,Btk activity after incubation of the kinase in the absence or presenceof a range of concentrations of a candidate tyrosine kinase inhibitorcompound. Many acellular kinase assays are available. See, e.g., seeKuzmic et al. (2000) Anal. Biochem, 286, 45-50.

Cellular functional assays for tyrosine kinase inhibition includemeasuring one or more cellular endpoints in response to stimulating asignaling pathway that is mediated by the tyrosine kinase (e.g., BCRactivation in Ramos cells) in the absence or presence of a range ofconcentrations of a candidate tyrosine inhibitor compounds. For example,in the case of Btk, useful endpoints include, e.g., autophosphorylationof Btk, phosphorylation of a Btk target protein (e.g., PLC-γ), andcytoplasmic calcium flux, in response to BCR activation.

High throughput assays for many acellular biochemical assays (e.g.,kinase assays) and cellular functional assays (e.g., calcium flux) areavailable. In addition, high throughput screening systems arecommercially available (see, e.g., Zymark Corp., Hopkinton, Mass.; AirTechnical Industries, Mentor, Ohio; Beckman Instruments, Inc. Fullerton,Calif.; Precision Systems, Inc., Natick, Mass., etc.). These systemstypically automate entire procedures including all sample and reagentpipetting, liquid dispensing, timed incubations, and final readings ofthe microplate in detector(s) appropriate for the assay. Automatedsystems thereby allow the identification and characterization of a largenumber of tyrosine kinase inhibitor compounds without undue effort.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. All patents, patentapplications, published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. Standardtechniques can be used for recombinant DNA, oligonucleotide synthesis,and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques can be performede.g., using kits of manufacturer's specifications or as commonlyaccomplished in the art or as described herein. The foregoing techniquesand procedures can be generally performed of conventional methods wellknown in the art and as described in various general and more specificreferences that are cited and discussed throughout the presentspecification.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group that hasat least one carbon-carbon double bond, and an “alkyne” moiety refers toa group that has at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic. Depending on the structure, an alkyl group can be amonoradical or a diradical (i.e., an alkylene group).

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to andincluding 10 carbon atoms, although the present definition also coversthe occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₄ alkyl” or similar designations. By way of exampleonly, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from among methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Thus C₁-C₄ alkyl includes C₁-C₂ alkyl and C₁-C₃ alkyl. Alkyl groups canbe substituted or unsubstituted. Typical alkyl groups include, but arein no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As used herein, the term “non-cyclic alkyl” refers to an alkyl that isnot cyclic (i.e., a straight or branched chain containing at least onecarbon atom). Non-cyclic alkyls can be fully saturated or can containnon-cyclic alkenes and/or alkynes. Non-cyclic alkyls can be optionallysubstituted.

The term “alkylamine” refers to the —N(alkyl)xHy group, where x and yare selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached, canoptionally form a cyclic ring system.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═C(R)—R, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. The alkenyl moiety may bebranched, straight chain, or cyclic (in which case, it would also beknown as a “cycloalkenyl” group). Depending on the structure, an alkenylgroup can be a monoradical or a diradical (i.e., an alkenylene group).Alkenyl groups can be optionally substituted. Non-limiting examples ofan alkenyl group include —CH═CH2, —C(CH3)=CH2, —CH═CHCH3, —C(CH3)=CHCH3,—CH═CH—, —C(CH3)=CH—, —CH═CHCH2-, —CH═CHCH2CH₂— and —C(CH3)=CHCH2-.Alkenyl groups, unless otherwise stated, may have 2 to 10 carbons.

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group, which may be the same or different. The“R” portion of the alkynyl moiety may be branched, straight chain, orcyclic. Depending on the structure, an alkynyl group can be amonoradical or a diradical (i.e., an alkynylene group). Alkynyl groupscan be optionally substituted. Non-limiting examples of an alkynyl groupinclude, but are not limited to, —C≡CH, —C≡CCH3, —C≡CCH2CH3, —C≡C—, and—C≡CCH2-. Alkynyl groups, unless otherwise stated, may have 2 to 10carbons.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith at least one alkoxy group, as defined herein.

An “alkenyloxy” group refers to a (alkenyl)O— group, where alkenyl is asdefined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed by five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both carbocyclic aryl (e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,fluorenyl, and indenyl. Depending on the structure, an aryl group can bea monoradical or a diradical (i.e., an arylene group).

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

“Aralkyl” or “arylalkyl” means an alkyl radical, as defined herein,substituted with an aryl group. Non-limiting aralkyl groups include,benzyl, phenethyl, and the like.

“Aralkenyl” means an alkenyl radical, as defined herein, substitutedwith at least one aryl group, as defined herein.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “carbocyclic” or “carbocycle” refers to a compound whichcontains one or more covalently closed ring structures, and that theatoms forming the backbone of the ring are all carbon atoms. The termthus distinguishes carbocyclic from heterocyclic rings in which the ringbackbone contains at least one atom which is different from carbon.Carbocycles include cycloalkyls and aryls.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and may be saturated, partiallyunsaturated, or fully unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms. Illustrative examples of cycloalkylgroups include the following moieties:

and the like. Depending on the structure, an cycloalkyl group can be amonoradical or a diradical (e.g., an cycloalkylene group).

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-limiting cycloalkylalkyl groups includecyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl,and the like.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are known to those of skill in the art and can readily befound in reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another. The terms“fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxygroups, respectively, in which the halo is fluorine. In certainembodiments, haloalkyls are optionally substituted.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms are selectedfrom an atom other than carbon, e.g., oxygen, nitrogen, sulfur, silicon,phosphorus or combinations thereof.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. The polycyclicheteroaryl group may be fused or non-fused. Illustrative examples ofheteroaryl groups include the following moieties:

-   -   and the like. Depending on the structure, a heteroaryl group can        be a monoradical or a diradical (i.e., a heteroarylene group).

“Heteroarylalkyl” or “heteroaralkyl” refers to an alkyl group, asdefined herein, substituted with a heteroaryl, as defined herein.

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three, four, five, six, seven, eight, nine, or morethan nine atoms. Heterocycloalkyl rings can be optionally substituted.In certain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples of heterocycloalkyls include, but arenot limited to, lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloaklene group).

“Heterocycloalkylalkyl” refers to an alkyl group, as defined herein,substituted with a heterocycloalkyl, as defined herein.

The term “heterocycle” refers to hetero aromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Herein, whenever the number of carbonatoms in a heterocycle is indicated (e.g., C₁-C₆ heterocycle), at leastone other atom (the heteroatom) must be present in the ring.Designations such as “C₁-C₆ heterocycle” refer only to the number ofcarbon atoms in the ring and do not refer to the total number of atomsin the ring. It is understood that the heterocylic ring can haveadditional heteroatoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Inheterocycles that have two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Binding to a heterocycle can be at aheteroatom or via a carbon atom. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one. Depending on thestructure, a heterocycle group can be a monoradical or a diradical(i.e., a heterocyclene group). Phosphorous-containing rings include, butare not limited to, 1-oxo-phospholanyl, 1-methyl-1-oxo-phosphinan-4-yl,1-phenyl-1-oxo-phosphinan-4-yl,1-(cyclopropylmethyl)-1-oxo-phosphinan-4-yl,4-methyl-4-oxo-[1,4]azaphosphinan-1-yl,4-phenyl-4-oxo-[1,4]azaphosphinan-1-yl, and4-(cyclopropylmethyl)-4-oxo-[1,4]azaphosphinan-1-yl.

As used herein,“1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene”refers to the following structure:

As used herein,“1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene”refers to the following structure:

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “sulfinyl” group refers to a —S(═O)—R.

A “sulfonyl” group refers to a —S(═O)₂—R.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

As used herein, the term “O-carboxy” or “acyloxy” refers to a group offormula RC(═O)O—.

“Alkylcarbonyloxy” refers to a (alkyl)-C(═O)O— group.

As used herein, the term “alkoxycarbonyl” refers to a group of formula—C(═O)OR.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH3.

“Acyl” refers to the group —C(O)R.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X3CS(═O)2- where X is a halogen.

As used herein, the term “cyano” refers to a group of formula —CN.

“Cyanoalkyl” means an alkyl radical, as defined herein, substituted withat least one cyano group.

As used herein, the term “alkylaminosulfonyl” refers to a group offormula —S(═O)₂NH(alkyl).

As used herein, the term “dialkylaminosulfonyl” refers to a group offormula —S(═O)₂N(alkyl)₂.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(═O)₂NH2.

As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to agroup of formula RS(═O)₂NH—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)NR2.

As used herein, the term “alkylaminocarbonyloxy” refers to a—OC(O)NH(alkyl) group.

As used herein, the term “dialkylaminocarbonyloxy” refers to a—OC(O)N(alkyl)₂ group.

“Aminocarbonyloxy” refers to a —OC(O)NH2 group.

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formula—OC(═S)NR2.

As used herein, the term “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)NR2.

As used herein, the term “alkylaminocarbonyl” refers to a group offormula —C(═O)NH(alkyl).

As used herein, the term “dialkylaminocarbonyl” refers to a group offormula —C(═O)N(alkyl)₂.

“Aminocarbonyl” refers to a —CONH2 radical.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

“Alkylcarbonylamino” refers to (alkyl)C(═O)NH—.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic heterocycle (bonded through a ring carbon).

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, carbonyl, isocyanato, thiocyanato, isothiocyanato, nitro,perhaloalkyl, fluoroalkyl, silyl, and amino, including mono- anddi-substituted amino groups, and the protected derivatives thereof. Byway of example an optional substituents may be LsRs, wherein each Ls isindependently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—,—NHC(O)O—, -(substituted or unsubstituted C1-C6 alkyl), or -(substitutedor unsubstituted C2-C6 alkenyl); and each Rs is independently selectedfrom H, (substituted or unsubstituted C₁-C₄alkyl), (substituted orunsubstituted C3-C6cycloalkyl), heteroaryl, or heteroalkyl. Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Compounds

Compounds that inhibit the activity of tyrosine kinase(s) can play arole in restoring or promoting health. In certain embodiments, tyrosinekinase inhibitor compounds provided herein are useful in treating any ofa variety of diseases, disorders or conditions. In certain embodiments,compounds provided herein are Btk inhibitor compounds.

Described herein are compounds that inhibit the activity of tyrosinekinase(s), such as Btk. Also described herein are pharmaceuticallyacceptable salts, pharmaceutically acceptable solvates, pharmaceuticallyactive metabolites, and pharmaceutically acceptable prodrugs of suchcompounds.

Pharmaceutical compositions that include at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, are provided. In some embodiments, whencompounds disclosed herein contain an oxidizable nitrogen atom, thenitrogen atom can be converted to an N-oxide by methods well known inthe art.

Compounds provided herein are inhibitors of tyrosine kinase activity,such as Btk. In one embodiment, provided herein is a compound of Formula(Ia). Formula (Ia) is as follows:

wherein:

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), —SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;        -   where each R⁷ is independently selected from among hydrogen,            optionally substituted alkyl, optionally substituted            alkenyl, optionally substituted alkynyl, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, and            heterocycloalkylalkyl;        -   A¹ is alkylene, alkenylene, or alkynylene;        -   R^(8a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl;        -   R^(8b) is hydrogen or R^(8a);        -   R⁶ is optionally substituted alkyl, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;        -   R³³ is substituted alkyl, substituted alkenyl, substituted            alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or            heterocycloalkylalkyl; and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(1a), are independently            optionally substituted with one, two, three, four, or five            halo;    -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heteroaryl, heteroaralkyl, heterocycloalkyl, or        heterocycloalkylalkyl or —X^(1a)—Y1-X^(1b)-Q¹ where        -   X^(1a) is a bond, alkylene, alkenylene, alkynylene,            cycloalkylene, or heterocycloalkylene where the alkylene,            alkenylene, and alkynylene are optionally substituted with            one, two, three, four, or five halo or one or two hydroxy;        -   Y¹ is a bond, —O—, —S(O)_(n1)— (where n1 is 0, 1, or 2),            —C(O)—, —NR¹⁸—, —NR¹⁸C(O)—, —NR¹⁸C(O)NR¹⁸—,            —NR¹⁸C(═NR¹⁸)NR¹⁸—, —C(O)NR—, —OC(O)—, —C(O)O—,            —C(O)N(R¹⁸)N═CR²⁷—, —NR¹⁸SO₂—, —SO₂NR¹⁸—, —C(R²⁷)(═NO)—,            —C(R²⁷)═NNR¹⁸—, —C(R²⁷)═NNR¹⁸C(O)—, —C(R²⁷)═NNR¹⁸C(O)NR¹⁸—,            —NR¹⁸C(O)O—, or —OC(O)NR¹⁸—;            -   where R¹⁸ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, hydroxy, alkoxy, or alkenyloxy;            -   R²⁷ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl; and            -   where alkyl, alkenyl, and alkynyl, either alone or as                part of another group within Y¹, are independently                optionally substituted with one, two, three, four, or                five halo;        -   X^(1b) is a bond, alkylene, alkenylene, alkynylene,            cycloalkylene, or heterocycloalkylene where the alkylene,            alkenylene, and alkynylene are optionally substituted with            one, two, three, four, or five halo or one or two hydroxy;        -   Q¹ is Z where Z is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(Y^(10a)R^(60a))(Y^(10b)R⁶⁰),            —P(E)(Y^(10e)R^(60a))(Z¹⁰R⁶¹), or an optionally substituted            ring system where one ring member is —P(=E)(R¹⁰⁰)—;            -   E is oxygen or sulfur;            -   Y^(10a) and Y^(10b) are independently a single bond,                —O—, —S—, or —NR^(62a)— where R^(62a) is hydrogen,                hydroxy, alkoxy, alkenyloxy, optionally substituted                alkyl, optionally substituted alkenyl, or optionally                substituted alkynyl;            -   R^(60a) and R^(60b) are independently hydrogen,                optionally substituted alkyl, optionally substituted                alkenyl, optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b), respectively, is —O—, —S—, or —NR^(62a)—;            -   R^(60a) and R^(60b) are independently optionally                substituted alkyl, optionally substituted alkenyl,                optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b), respectively, is a single bond;            -   Y^(10e) is —O—, —S—, or —NR^(62a)—;            -   Z¹⁰ is alkylene, alkenylene, alkynylene, —O—, —S—, or                —NR^(62a)—;            -   R⁶¹ is hydrogen, acyl, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl; or            -   R⁶¹ is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b));            -   R¹⁰⁰ is a single bond from the phosphorous atom to                X^(1b), or R¹⁰⁰ is halo, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, optionally substituted phenyl, optionally                substituted phenylalkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,                heteroaralkyl, —OR¹⁰¹, or —NR^(102a)R^(102b); and                -   where the alkyl, alkenyl, and alkynyl within R¹⁰⁰,                    either alone or as part of another substituent, are                    independently optionally substituted with one, two,                    three, four, or five halo;                -   R¹⁰¹ is hydrogen, optionally substituted alkyl,                    optionally substituted alkenyl, or optionally                    substituted alkynyl;                -   R^(102a) and R^(102b) are independently hydrogen,                    optionally substituted alkyl, optionally substituted                    alkenyl, optionally substituted alkynyl, aryl,                    aralkyl, heteroaryl, hetero aralkyl, cycloalkyl,                    cycloalkylalkyl, heterocycloalkyl, or                    heterocycloalkylalkyl;    -   R^(1c) and R^(1d) are —X^(1a)—Z where X^(1a) and Z are as        defined above;    -   R^(2a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy,        alkoxy, alkenyloxy, optionally substituted phenyl, cyano,        optionally substituted phenyl, heteroaryl, —NR^(14a)R^(18a),        -(A¹)-NR^(12a)R^(12b), —NR^(13a)C(O)R^(13b),        -(A¹)-NR^(13a)C(O)R^(13b), —C(O)NR^(14a)R^(14b), or        -(A¹)-C(O)NR^(12a)R^(12b); and    -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or as        part of another group within R^(2a), are independently        optionally substituted with one, two, three, four, or five halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;    -   R^(2b) is —X^(2a)—Y²—X^(2b)-Q² where        -   X^(2a) is a bond, alkylene, alkenylene, or alkynylene where            the alkylene, alkenylene, and alkynylene are optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy;        -   Y² is a bond, —O—, —S(O)_(n1)— (where n1 is 0, 1, or 2),            —C(O)—, —NR⁴⁵—, —NR⁴⁵C(O)—, —NR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(═NR⁴⁵)NR⁴⁵—, —C(O)NR⁴⁵—, —OC(O)—, —C(O)O—,            —C(O)N(R⁴⁵)N═CR⁷⁴—, —NR⁴⁵SO₂—, —SO₂NR⁴⁵—, —C(R⁷⁴)(═NO)—,            —C(R⁷⁴)═NNR⁴⁵—, —C(R⁷⁴)═NNR⁴⁵C(O)—, —C(R⁷⁴)═NNR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(O)O—, or —OC(O)NR⁴⁵—;            -   where R⁴⁵ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, hydroxy, alkoxy, or alkenyloxy;            -   R⁷⁴ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, or optionally                substituted alkynyl; and            -   where alkyl, alkenyl, and alkynyl, either alone or as                part of another group within Y², are independently                optionally substituted with one, two, three, four, or                five halo;        -   X^(2b) is a bond; and        -   Q² is hydrogen, cyano, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl,            cycloalkyl, heterocycloalkyl, or heteroaryl; or    -   R^(2a) and R^(2b) together form cycloalkyl, heterocycloalkyl,        aryl, or heteroaryl; and    -   R³ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl,        alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        -(A⁵)-S(O)₀₋₂R⁵³, -(A⁵)-N(R⁵⁴)₂, -(A⁵)-OR⁵⁵, -(A⁵)-OC(O)R⁵³,        -(A⁵)-C(O)R⁵³, -(A⁵)-C(O)OR⁵⁵, -(A⁵)-C(O)N(R⁵⁴)₂,        -(A5)-NR⁵⁴C(O)R⁵³, -(A⁵)-S(O)₂N(R⁵⁴)₂, -(A⁵)-NR⁵⁴S(O)₂R⁵³,        -(A⁵)-OC(O)N(R⁵⁴)₂, -(A⁵)-NR⁵⁴C(O)OR⁵⁵, or        -(A⁵)-NR⁵⁴C(O)N(R⁵⁴)₂;        -   A⁵ is a bond, alkylene, alkenylene, or alkynylene;        -   R⁵³ is optionally substituted alkyl, optionally substituted            alkenyl, optionally substituted alkynyl, aryl, aralkyl,            heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl;        -   R⁵⁴ is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,            heteroaryl, or heteroaralkyl;        -   R⁵⁵ is hydrogen or R⁵³; and        -   where alkyl, alkenyl, alkynyl, alkylene, alkenylene, and            alkynylene, either alone or as part of another group within            R³, are independently optionally substituted with one, two,            three, four, or five halo; and    -   pharmaceutically acceptable salts, pharmaceutically acceptable        solvates, pharmaceutically acceptable metabolites or        pharmaceutically acceptable prodrugs thereof.

In one embodiment, provided herein are compounds of Formula (Ia),wherein R³ is hydrogen and J is —NR5- where R5 is hydrogen or anoptionally substituted alkyl. In another embodiment, J is —N(methyl)-.

In another embodiment, Q1 is an optionally substituted ring system whereone ring member is —P(=E)(R100)-.

In some embodiments, R1b is —X1a-Y1-X¹b-Q1. In other embodiments, Ya is—NR1aR1b where R1a is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, hydroxy, alkoxy,alkenyloxy, or acyl; and R1b is aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, orheterocycloalkylalkyl. In yet other embodiments, Ya is —NR1aR1b whereR1a is hydrogen and R1b is aryl.

In another embodiment, provided herein is a compound of Formula (Ib).Formula (Ib) is as

wherein:

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), —SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;            -   where each R⁷ is independently selected from among                hydrogen, optionally substituted alkyl, optionally                substituted alkenyl, optionally substituted alkynyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and                heterocycloaklalkyl;            -   A¹ is alkylene, alkenylene, or alkynylene;            -   R^(8a) is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or hetero cycloalkylalkyl;            -   R^(8b) is hydrogen or R^(8a);            -   R⁶ is optionally substituted alkyl, cycloalkyl,                cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl;            -   R³³ is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or hetero cycloalkylalkyl; and            -   where alkyl, alkenyl, alkynyl, and alkylene, either                alone or as part of another group within R^(1a), are                independently optionally substituted with one, two,                three, four, or five halo;        -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            heteroaryl, heteroaralkyl, heterocycloalkyl, or            heterocycloalkylalkyl; or        -   R^(1a) and R^(1b) together with the nitrogen to which they            are attached form heterocycloalkyl or heteroaryl;        -   R^(1c) and R^(1d) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl, acyl,            cycloalkyl, cycloalkylalkyl, heterocycloalkyl,            heterocycloalkylalkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, or -(A¹⁸)-C(O)NR^(50a)R^(50b);            -   A¹⁸ is alkylene, alkenylene, or alkynylene; and            -   R^(50a) and R^(50b) are independently hydrogen,                optionally substituted alkyl, aryl, aralkyl, heteroaryl,                heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl); and        -   where alkyl, alkenyl, and alkylene either alone or as part            of another group within R^(1a), R^(1b), R^(1c) and R^(1d),            are independently optionally substituted with one, two,            three, four, or five halo;    -   R^(2a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy,        alkoxy, alkenyloxy, optionally substituted phenyl, cyano,        optionally substituted phenyl, heteroaryl, —NR^(14a)R^(14b),        -(A¹)-NR^(12a)R^(12b), —NR^(13a)C(O)R^(13b),        -(A¹)-NR^(13a)C(O)R^(13b), —C(O)NR^(14a)R^(14b), or        -(A¹)-C(O)NR^(12a)R^(12b); and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(2a), are independently            optionally substituted with one, two, three, four, or five            halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;    -   R^(2b) is —X^(2a)—Y²—X^(2b)-Q³ where        -   X^(2a) is a bond, alkylene, alkenylene, or alkynylene where            the alkylene, alkenylene, and alkynylene are optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy;        -   Y² is a bond, —O—, —S(O)_(n1)— (where n1 is 0, 1, or 2),            —C(O)—, —NR⁴⁵—, —NR⁴⁵C(O)—, —NR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(═NR⁴⁵)NR⁴⁵—, —C(O)NR⁴⁵—, —OC(O)—, —C(O)O—,            —C(O)N(R⁴⁵)N═CR⁷⁴—, —NR⁴⁵SO₂—, —SO₂NR⁴⁵—, —C(R⁷⁴)(═NO)—,            —C(R⁷⁴)═NNR⁴⁵—, —C(R⁷⁴)═NNR⁴⁵C(O)—, —C(R⁷⁴)═NNR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(O)O—, or —OC(O)NR⁴⁵—;            -   where R⁴⁵ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, hydroxy, alkoxy, or alkenyloxy;            -   R⁷⁴ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, or optionally                substituted alkynyl; and            -   where alkyl, alkenyl, and alkynyl, either alone or as                part of another group within Y², are independently                optionally substituted with one, two, three, four, or                five halo;        -   X^(2b) is a bond, alkylene, alkenylene, alkynylene,            cycloalkylene, or heterocycloalkylene where alkylene,            alkenylene, and alkynylene are independently optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy; and        -   Q³ is Z where Z is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(=E)(Y^(10e)R^(60a))(Z¹⁰R⁶¹), or an optionally substituted            ring system where one ring member is —P(=E)(R¹⁰⁰)—;            -   E is oxygen or sulfur;            -   Y^(10a) and Y^(10b) are independently a single bond,                —O—, —S—, or —NR^(62a)— where R^(62a) is hydrogen,                hydroxy, alkoxy, alkenyloxy, optionally substituted                alkyl, optionally substituted alkenyl, or optionally                substituted alkynyl;            -   R^(60a) and R^(60b) are independently hydrogen,                optionally substituted alkyl, optionally substituted                alkenyl, optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b) respectively, is —O—, —S—, or —NR^(62a)—;            -   R^(60a) and R^(60b) are independently optionally                substituted alkyl, optionally substituted alkenyl,                optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b), respectively, is a single bond;            -   Y^(10e) is —O—, —S—, or —NR^(62a)—;            -   Z¹⁰ is alkylene, alkenylene, alkynylene, —O—, —S—, or                —NR^(62a)—;            -   R⁶¹ is hydrogen, acyl, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl; or            -   R⁶¹ is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b));            -   R¹⁰⁰ is a single bond from the phosphorous atom to                X^(1b), or R¹⁰⁰ is halo, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, optionally substituted phenyl, optionally                substituted phenylalkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,                heteroaralkyl, —OR¹⁰¹, or —NR^(102a)R^(102b); and                -   where the alkyl, alkenyl, and alkynyl within R¹⁰⁰,                    either alone or as part of another substituent, are                    independently optionally substituted with one, two,                    three, four, or five halo;                -   R¹⁰¹ is hydrogen, optionally substituted alkyl,                    optionally substituted alkenyl, or optionally                    substituted alkynyl;                -   R^(102a) and R^(102b) are independently hydrogen,                    optionally substituted alkyl, optionally substituted                    alkenyl, optionally substituted alkynyl, aryl,                    aralkyl, heteroaryl, hetero aralkyl, cycloalkyl,                    cycloalkylalkyl, heterocycloalkyl, or                    heterocycloalkylalkyl;    -   R³ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl,        alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        -(A⁵)-S(O)₀₋₂R⁵³, -(A⁵)-N(R⁵⁴)₂, -(A⁵)-OR⁵⁵, -(A⁵)-OC(O)R⁵³,        -(A⁵)-C(O)R⁵³, -(A⁵)-C(O)OR⁵⁵, -(A⁵)-C(O)N(R⁵⁴)₂,        -(A5)-NR⁵⁴C(O)R⁵³, -(A⁵)-S(O)₂N(R⁵⁴)₂, -(A⁵)-NR⁵⁴S(O)₂R⁵³,        -(A⁵)-OC(O)N(R⁵⁴)₂, -(A⁵)-NR⁵⁴C(O)OR⁵⁵, or        -(A⁵)-NR⁵⁴C(O)N(R⁵⁴)₂;        -   A⁵ is a bond, alkylene, alkenylene, or alkynylene;        -   R⁵³ is optionally substituted alkyl, optionally substituted            alkenyl, optionally substituted alkynyl, aryl, aralkyl,            heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl;        -   R⁵⁴ is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,            heteroaryl, or heteroaralkyl;        -   R⁵⁵ is hydrogen or R⁵³; and        -   where alkyl, alkenyl, alkynyl, alkylene, alkenylene, and            alkynylene, either alone or as part of another group within            R³, are independently optionally substituted with one, two,            three, four, or five halo; and    -   pharmaceutically acceptable salts, pharmaceutically acceptable        solvates, pharmaceutically acceptable metabolites or        pharmaceutically acceptable prodrugs thereof.

In another embodiment, provided herein are compounds of Formula (Ib),wherein R³ is hydrogen and J is —NR5- where R5 is hydrogen or anoptionally substituted alkyl. In another embodiment, J is —N(methyl)-.

In some other embodiments, Ya is —NR1aR1b where R1a is hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, hydroxy, alkoxy, alkenyloxy, or acyl; and R1b isaryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl. In another embodiment, Ya is—NR1 aR1b where R1a is hydrogen or alkyl and R1b is aryl or heteroaryl.In some other embodiments, Ya is —NR1 aR1b where R1a is hydrogen and R1bis aryl. In yet some other embodiments, Ya is —NH(aryl). In furtherembodiments, Ya is 4-fluoro-2-methylphenylamino or2,6-dichlorophenylamino. In other embodiments, Q3 is an optionallysubstituted ring system where one ring member is —P(=E)(R100)-.

In other embodiments, R2a is optionally substituted alkyl. In some otherembodiments, R2a is methyl; and R2b is —X2a-Y2-X2b-Q2 where X2a isalkenylene. In yet other embodiments, R2a is methyl; and R2b is—X2a-Y2-X2b-Q2 where X2a is —CH2CH═CH—. In some other embodiments, Y2 isa bond, —C(O)NR45-, or —C(O)NH—. In other embodiments, X2b is a bond,and Q2 is an optionally substituted ring system where one ring member is—P(=E)(R100)-. In some other embodiments, R2a is methyl; and R2b is—X2a-Y2-X2b-Q2 where X2a is —CH2CH═CH—, Y2 is a bond, or —C(O)NH—; X2bis a bond, and Q2 is an optionally substituted ring system where onering member is —P(=E)(R100)-.

In some embodiments, R2a is located at the 6-position and R2b is locatedat the 7-position.

In some embodiments, Y2 is a bond and Q2 is a saturated, monocyclicgroup of 6 ring atoms in which one of the ring atoms is nitrogen andanother ring member is —P(═O)(R100)- and where the nitrogen is the pointof attachment to X2b. In other embodiments, R100 is alkyl, aryl,aralkyl, cycloalkyl, or cycloalkylalkyl. In further embodiments, Q2 is4-methyl-4-oxo-4□5-[1,4]azaphosphinan-1-yl;4-oxo-4-phenyl-4□5-[1,4]azaphosphinan-1-yl;4-(4-fluorophenylmethyl)-4-oxo-4□5-[1,4]azaphosphinan-1-yl;4-(cyclopropylmethyl)-4-oxo-4□5-[1,4]azaphosphinan-1-yl; or4-(cyclopropyl)-4-oxo-4□5-[1,4]azaphosphinan-1-yl.

In some other embodiments, Y2 is —C(O)NH— and Q2 is a saturatedmonocyclic hydrocarbon radical of 6 ring atoms where one ring member is—P(═O)(R100)-. In other embodiments, R100 is alkyl or aryl. In otherembodiments, Y2 is —C(O)NH— and Q2 is a saturated monocyclic hydrocarbonradical of 6 ring atoms where one ring member is —P(═O)(R100)-; and R100is alkyl or aryl. In yet other embodiments, Q2 is1-oxo-1-methyl-1□5-phosphinan-4-yl,1-oxo-1-trans-phenyl-1□5-phosphinan-4-yl, or1-oxo-1-cis-phenyl-1□5-phosphinan-4-yl.

In another embodiment, J is —NR5-; where R5 is hydrogen; R2a isoptionally substituted alkyl; R3 is hydrogen; Ya is —NR1aR1b where R1ais hydrogen or alkyl and R1b is aryl or heteroaryl; R2b is—X2a-Y2-X2b-Q3 where X2a is alkenylene, Y2 is a bond or —C(O)NH—, X2b isa bond, and Q3 is an optionally substituted ring system where one ringmember is —P(=E)(R100)- and E is oxygen and R100 is alkyl, aryl,aralkyl, cycloalkyl, or cycloalkylalkyl.

In another embodiment, R2a is optionally substituted alkyl; and R2b is—X2a-Y2-X2b-Q2 where X2a is alkenylene, Y2 is a bond or —C(O)NR45-, X2bis a bond, and Q2 is an optionally substituted ring system where onering member is —P(=E)(R100)-.

In another embodiment, provided herein is a compound of Formula (Ic).Formula (Ic) is as follows:

wherein:

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), —SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;            -   where each R⁷ is independently selected from among                hydrogen, optionally substituted alkyl, optionally                substituted alkenyl, optionally substituted alkynyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and                heterocycloalkylalkyl;            -   A¹ is alkylene, alkenylene, or alkynylene;            -   R^(8a) is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl;            -   R^(8b) is hydrogen or R^(8a);            -   R⁶ is optionally substituted alkyl, cycloalkyl,                cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl;            -   R³³ is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl; and            -   where alkyl, alkenyl, alkynyl, and alkylene, either                alone or as part of another group within R^(1a), are                independently optionally substituted with one, two,                three, four, or five halo;        -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            heteroaryl, heteroaralkyl, heterocycloalkyl, or            heterocycloalkylalkyl; or        -   R^(1a) and R^(1b) together with the nitrogen to which they            are attached form heterocycloalkyl or heteroaryl;        -   R^(1c) and R^(1d) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl, acyl,            cycloalkyl, cycloalkylalkyl, heterocycloalkyl,            heterocycloalkylalkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, or -(A¹⁸)-C(O)NR^(50a)R^(50b);            -   A^(1b) is alkylene, alkenylene, or alkynylene; and            -   R^(50a) and R^(50b) are independently hydrogen,                optionally substituted alkyl, aryl, aralkyl, heteroaryl,                heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl); and        -   where alkyl, alkenyl, and alkylene either alone or as part            of another group within R^(1a), R^(1b) R^(1c) and R^(1d),            are independently optionally substituted with one, two,            three, four, or five halo;    -   R^(2a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy,        alkoxy, alkenyloxy, optionally substituted phenyl, cyano,        optionally substituted phenyl, heteroaryl, —NR^(14a)R^(14b),        -(A¹)-NR^(12a)R^(12b), —NR^(13a)C(O)R^(13b),        -(A¹)-NR^(13a)C(O)R^(13b), —C(O)NR^(14a)R^(14b), or        (A¹)-C(O)NR^(12a)R^(12b); and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(2a), are independently            optionally substituted with one, two, three, four, or five            halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;    -   R^(2b) is —X^(2a)—Y²—X^(2b)-Q² where        -   X^(2a) is a bond, alkylene, alkenylene, or alkynylene where            the alkylene, alkenylene, and alkynylene are optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy;        -   Y² is a bond, —O—, —S(O)_(n1)— (where n1 is 0, 1, or 2),            —C(O)—, —NR⁴⁵—, —NR⁴⁵C(O)—, —NR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(═NR⁴⁵)NR⁴⁵—, —C(O)NR⁴⁵—, —OC(O)—, —C(O)O—,            —C(O)N(R⁴⁵)N═CR⁷⁴—, —NR⁴⁵SO₂—, —SO₂NR⁴⁵—, —C(R⁷⁴)(═NO)—,            —C(R⁷⁴)═NNR⁴⁵—, —C(R⁷⁴)═NNR⁴⁵C(O)—, —C(R⁷⁴)═NNR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(O)O—, or —OC(O)NR⁴⁵—;            -   where R⁴⁵ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, hydroxy, alkoxy, or alkenyloxy;            -   R⁷⁴ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, or optionally                substituted alkynyl; and            -   where alkyl, alkenyl, and alkynyl, either alone or as                part of another group within Y², are independently                optionally substituted with one, two, three, four, or                five halo;        -   X^(2b) is a bond; and        -   Q² is hydrogen, cyano, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl,            cycloalkyl, heterocycloalkyl, or heteroaryl;    -   R³ is —X^(3a)—Y³—X^(3b)-Q⁴ where        -   X^(3a) is a bond, alkylene, alkenylene, or alkynylene where            alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or one or two hydroxy,        -   Y³ is —C(O)—, or —NR⁵¹— where R⁵¹ is hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl and where alkyl,            alkenyl, and alkynyl, either alone or as part of another            group within Y³, are independently optionally substituted            with one, two, three, four, or five halo,        -   X^(3b) is a bond, alkylene, alkenylene, alkynylene,            cycloalkylene, or heterocycloalkylene where alkylene,            alkenylene, and alkynylene are independently optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy, and        -   Q⁴ is Z where Z is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(=E)(Y^(10e)R^(60a))(Z¹⁰R⁶¹), or an optionally substituted            ring system where one ring member is —P(=E)(R¹⁰⁰)—;            -   E is oxygen or sulfur;            -   Y^(10a) and Y^(10b) are independently a single bond,                —O—, —S—, or where R^(62a) is hydrogen, hydroxy, alkoxy,                alkenyloxy, optionally substituted alkyl, optionally                substituted alkenyl, or optionally substituted alkynyl;            -   R^(60a) and R^(60b) are independently hydrogen,                optionally substituted alkyl, optionally substituted                alkenyl, optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b) respectively, is —O—, —S—, or —NR^(62a)—;            -   R^(60a) and R^(60b) are independently optionally                substituted alkyl, optionally substituted alkenyl,                optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b) respectively, is a single bond;            -   Y^(10e) is —O—, —S—, or —NR^(62a)—;            -   Z¹⁰ is alkylene, alkenylene, alkynylene, —O—, —S—, or                —NR^(62a)—;            -   R⁶¹ is hydrogen, acyl, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or hetero                cycloalkylalkyl; or            -   R⁶¹ is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b));            -   R¹⁰⁰ is a single bond from the phosphorous atom to                X^(1b), or R¹⁰⁰ is halo, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, optionally substituted phenyl, optionally                substituted phenylalkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,                heteroaralkyl, —OR¹⁰¹, or —NR^(102a)R^(102b); and                -   where the alkyl, alkenyl, and alkynyl within R¹⁰⁰,                    either alone or as part of another substituent, are                    independently optionally substituted with one, two,                    three, four, or five halo;                -   R¹⁰¹ is hydrogen, optionally substituted alkyl,                    optionally substituted alkenyl, or optionally                    substituted alkynyl;                -   R^(102a) and R^(102b) are independently hydrogen,                    optionally substituted alkyl, optionally substituted                    alkenyl, optionally substituted alkynyl, aryl,                    aralkyl, heteroaryl, hetero aralkyl, cycloalkyl,                    cycloalkylalkyl, heterocycloalkyl, or                    heterocycloalkylalkyl; and    -   pharmaceutically acceptable salts, pharmaceutically acceptable        solvates, pharmaceutically acceptable metabolites or        pharmaceutically acceptable prodrugs thereof.

In some embodiments, provided herein is a compound of Formula (Ic),wherein J is —NR5- where R⁵ is hydrogen or optionally substituted alkyl.In other embodiments, J is —N(methyl)-.

In another embodiment, Ya is —NR1aR1b where R1a is hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, hydroxy, alkoxy, alkenyloxy, or acyl; and R1b isaryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl. In other embodiments, Ya is—NR1 aR1b where R1a is hydrogen or alkyl; and R1b is aryl or heteroaryl.In other embodiments, Ya is —NH(aryl). In some other embodiments, Ya is4-fluoro-2-methylphenylamino or 2,6-dichlorophenylamino.

In another embodiment, Q4 is an optionally substituted ring system whereone ring member is —P(=E)(R100)-.

In one embodiment, provided herein is a compound that has a structure ofFormula (II). Formula (II) is as follows:

wherein:

-   -   R^(250a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, or optionally substituted alkynyl and where        alkyl, alkenyl, and alkynyl, are independently optionally        substituted with one, two, three, four, or five halo;    -   R^(250b) is —CH(═NOH), —C(H)═N—NHC(O)-Q²⁵⁰, or        —X^(250a)—Y²⁵⁰—X^(250b)-Q²⁵⁰ where        -   X^(250a) is alkylene, alkenylene, or alkynylene and where            alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or with one or two hydroxy;        -   Y²⁵⁰ is a bond, —S—, —S(O)—, —S(O)₂—, —C(O)O—, or —OC(O)—;        -   X^(250b) is a bond, alkylene, alkenylene, or alkynylene and            where alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or with one or two hydroxy;        -   Q²⁵⁰ is aryl or heteroaryl or Q²⁵⁰ is heterocycloalkyl            substituted with one or two groups selected from aryl, acyl,            heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl,            alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl,            alkylaminocarbonyl, dialkylaminocarbonyl, and            -(alkylene)-R²⁵¹;        -   R²⁵¹ is phenyl substituted with one, two, or three groups            selected from among halo, hydroxy, alkoxy, cyano,            alkylamino, dialkylamino, acyl, optionally substituted            alkyl, optionally substituted alkenyl, optionally            substituted alkynyl, alkylsulfonyl, alkenylsulfonyl,            alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl,            alkylaminocarbonyl, and dialkylaminocarbonyl;        -   and where alkylene, alkyl, alkenyl, and alkynyl, either            alone or as part of another group within R²⁵⁰, are            independently optionally substituted with one, two, three,            four, or five halo;    -   R^(350a) is hydrogen, hydroxy, alkoxy, optionally substituted        alkyl, optionally substituted alkenyl, or optionally substituted        alkynyl and where alkyl, alkenyl, and alkynyl, are independently        optionally substituted with one, two, three, four, or five halo;    -   R^(350b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heteroaryl, heteroaralkyl, heterocycloalkyl, or        heterocycloalkylalkyl and where the alkyl in aralkyl,        cycloalkylalkyl, heteroaralkyl, or heterocycloalkylalkyl;    -   R³⁰⁰ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, hetero        aralkyl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl,        alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino,        aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,        alkylsulfonylamino, or -A¹⁰⁰-R³⁰¹;        -   A¹⁰⁰ is alkylene or alkenylene; and        -   R³⁰¹ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl,            alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,            heteroaryl, hetero aralkyl, alkylsulfonyl, alkenylsulfonyl,            arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl,            acyloxy, alkoxycarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, alkylcarbonylamino, aminosulfonyl,            alkylaminosulfonyl, dialkylaminosulfonyl, or            alkylsulfonylamino; and        -   where alkyl, alkenyl, alkynyl, alkylene, alkenylene, and            alkynylene, either alone or as part of another group within            R³⁰⁰, are independently optionally substituted with one,            two, three, four, or five halo; and    -   R⁴⁰⁰ is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy, or        alkoxy and where alkyl, alkenyl, and alkynyl, either alone or as        part of another group within R⁴⁰⁰, are independently optionally        substituted with one, two, three, four, or five halo; and        pharmaceutically acceptable salts, pharmaceutically acceptable        solvates, pharmaceutically acceptable metabolites or        pharmaceutically acceptable prodrugs thereof.

In another embodiment, provided herein is a compound of Formula (II),wherein:

wherein

-   -   R^(250a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, or optionally substituted alkynyl and where        alkyl, alkenyl, and alkynyl, are independently optionally        substituted with one, two, three, four, or five halo;    -   R^(250b) is —X^(250a)—Y²⁵⁰—X^(250b)-Q²⁵⁰ where        -   X^(250a) is alkylene, alkenylene, or alkynylene and where            alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or with one or two hydroxy;        -   Y²⁵⁰ is a bond, —S—, —S(O)—, —S(O)₂—, —C(O)O—, or —OC(O)—;        -   X^(250b) is a bond, alkylene, alkenylene, or alkynylene and            where alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or with one or two hydroxy;        -   Q²⁵⁰ is aryl or heteroaryl or Q²⁵⁰ is heterocycloalkyl            substituted with one or two groups selected from aryl, acyl,            heteroaryl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl,            alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl,            alkylaminocarbonyl, and dialkylaminocarbonyl, and where            alkylene, alkyl, alkenyl, and alkynyl, either alone or as            part of another group within R²⁵⁰, are independently            optionally substituted with one, two, three, four, or five            halo;    -   R^(350a) is hydrogen, hydroxy, alkoxy, optionally substituted        alkyl, optionally substituted alkenyl, or optionally substituted        alkynyl and where alkyl, alkenyl, and alkynyl, are independently        optionally substituted with one, two, three, four, or five halo;    -   R^(350b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,        heteroaryl, heteroaralkyl, heterocycloalkyl, or        heterocycloalkylalkyl and where the alkyl in aralkyl,        cycloalkylalkyl, heteroaralkyl, or heterocycloalkylalkyl;    -   R³⁰⁰ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, hetero        aralkyl, alkylsulfonyl, alkenylsulfonyl, arylsulfonyl,        alkylamino, dialkylamino, alkoxy, acyl, acyloxy, alkoxycarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino,        aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,        alkylsulfonylamino, or -A¹⁰⁰-R³⁰¹ (where A¹⁰⁰ is alkylene or        alkenylene and R³⁰¹ is hydrogen, halo, acyl, acylamino, acyloxy,        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, alkylsulfonyl, alkenylsulfonyl,        arylsulfonyl, alkylamino, dialkylamino, alkoxy, acyl, acyloxy,        alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,        alkylcarbonylamino, aminosulfonyl, alkylaminosulfonyl,        dialkylaminosulfonyl, or alkylsulfonylamino) and where alkyl,        alkenyl, alkynyl, alkylene, alkenylene, and alkynylene, either        alone or as part of another group within R³⁰⁰, are independently        optionally substituted with one, two, three, four, or five halo;        and    -   R⁴⁰⁰ is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy, or        alkoxy and where alkyl, alkenyl, and alkynyl, either alone or as        part of another group within R⁴⁰⁰, are independently optionally        substituted with one, two, three, four, or five halo; and    -   pharmaceutically acceptable salts, pharmaceutically acceptable        solvates, pharmaceutically acceptable metabolites or        pharmaceutically acceptable prodrugs thereof.

In another embodiment, R^(250a) is optionally substituted alkyl;R^(250b) is —CH(═NOH), —C(H)═N—NHC(O)-Q²⁵⁰, or—X^(250a)—Y²⁵⁰—X^(250b)-Q²⁵⁰ where X^(250a) is alkylene, alkenylene, oralkynylene and where alkylene, alkenylene, and alkynylene areindependently optionally substituted with one, two, three, four, or fivehalo or with one or two hydroxy; Y²⁵⁰ is a bond, —S(O)₂—, or —C(O)O—;X^(250b) is a bond; Q²⁵⁰ is aryl or heteroaryl or Q²⁵⁰ isheterocycloalkyl substituted with aryl, acyl, heteroaryl, alkylsulfonyl,arylsulfonyl, alkoxycarbonyl, dialkylaminosulfonyl, alkylaminocarbonyl,or -(alkylene)-R²⁵¹ (where R²⁵¹ is phenyl substituted with halo);R^(350a) is hydrogen; R^(350b) is aryl; R³⁰⁰ is hydrogen; and R⁴⁰⁰ isoptionally substituted alkyl.

In some other embodiments, R350a is hydrogen and R350b is aryl.

In yet some other embodiments, R³⁰⁰ is hydrogen and R^(250a) and R⁴⁰⁰are optionally substituted alkyl.

In some other embodiments, R^(250b) is R^(250b) is—X^(250a)—Y²⁵⁰—X^(250b)-Q²⁵⁰ where X^(250a) is —CH₂CH═CH—, Y²⁵⁰ is abond, X^(250b) is a bond, and Q²⁵⁰ is heterocycloalkyl substituted withone or two groups selected from aryl, acyl, heteroaryl, alkylsulfonyl,alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and-(alkylene)-R²⁵¹ (where R²⁵¹ is phenyl substituted with one, two, orthree groups selected from halo, hydroxy, alkoxy, cyano, alkylamino,dialkylamino, acyl, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, alkylsulfonyl, alkenylsulfonyl,alkoxycarbonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylaminocarbonyl, and dialkylaminocarbonyl) and where alkylene, alkyl,alkenyl, and alkynyl, either alone or as part of another group withinR²⁵⁰, are independently optionally substituted with one, two, three,four, or five halo; and R^(250b) is located at the 7-position. In yetother embodiments, Q²⁵⁰ is heterocycloalkyl substituted with one or twogroups selected from aryl, acyl, heteroaryl, alkylsulfonyl,alkenylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl,dialkylaminosulfonyl, and -(alkylene)-R²⁵¹ (where R²⁵¹ is phenylsubstituted with one, two, or three groups selected from halo, hydroxy,alkoxy, cyano, alkylamino, dialkylamino, acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,alkylsulfonyl, alkenylsulfonyl, alkoxycarbonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylaminocarbonyl, and dialkylaminocarbonyl).

In some other embodiments, Q250 is piperazin-1-yl substituted at the4-position of the piperazin-1-yl ring with one group selected from amongaryl, acyl, heteroaryl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl,alkylaminocarbonyl, and alkylaminosulfonyl. In yet other embodiments,Q250 is piperazin-1-yl substituted at the 4-position of thepiperazin-1-yl ring with one group selected from among aryl, acyl,heteroaryl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, andalkylaminosulfonyl.

In one aspect, provided herein are compounds of Formula (III):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or        1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;    -   L is —X^(250a)—Y²⁵⁰— or —Y²⁵⁰—X^(250a)—, wherein,        -   X^(250a) is a substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—, —C(═O)—, —NR⁴⁵—,            —NH—, —NHC(═O)—, —NR⁴⁵C(═O)—, —NR⁴⁵C(═O)NR⁴⁵—, —C(═O)NH—,            —C(═O)NR⁴⁵—, —OC(═O)—, —C(═O)O—, —NHSO₂—, —NR⁴⁵SO₂—,            —SO₂NH—, —SO₂NR⁴⁵—, —C(R⁴⁵)═NO—, —CH═NO—, —ON═CH—,            heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR⁴⁵C(═O)O—, or            —OC(═O)NR⁴⁵—;        -   where each R⁴⁵ is independently selected from among            hydrogen, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₃-C₈cycloalkyl, substituted or            unsubstituted C₂-C₆alkenyl, substituted or unsubstituted            C₂-C₆alkynyl;    -   M is N or CH;    -   W is

-   -   -   E is oxygen or sulfur;        -   R¹⁰⁰ is halogen, —OH, or an optionally substituted group            selected from among C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,            phenyl, C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl,            C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl,            C₁-C₄alkyl(C₂-C₈heterocycloalkyl), heteroaryl,            C₁-C₄alkyl(heteroaryl), C₁-C₆alkoxy, C₁-C₆alkenyloxy,            C₁-C₆alkynyloxy, or —NR^(102a)R^(102b);        -   R^(102a) and R^(102b) are independently hydrogen, or an            optionally substituted group selected from among C₁-C₆alkyl,            C₂-C₆alkenyl, C₂-C₆alkynyl, aryl, aralkyl, heteroaryl,            hetero aralkyl, C₃-C₈cycloalkyl,            C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl, and            C₁-C₄alkyl(C₂-C₈heterocycloalkyl);        -   R²⁰⁰ is an optionally substituted group selected from among            C₂-C₁₀acyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,            C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl, hetero            aralkyl, C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl,            arylsulfonyl, heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl,            aminosulfonyl, C₁-C₆alkylaminosulfonyl,            di(C₁-C₆alkyl)aminosulfonyl, and C₁-C₆alkylsulfonylamino;

    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl;

    -   n is 0, 1, or 2; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

For any and all of the embodiments, substituents can be selected fromamong from a subset of the listed alternatives. For example, in someembodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene.In other embodiments, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In other embodiment, Y250 is a bond, —O—, —S(═O)—, —S(═O)2-, —C(═O)—,—NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO2-,—SO2NH—, —NHC(═O)O—, or —OC(═O)NH—; E is O; and R350a is hydrogen, asubstituted or unsubstituted C1-C6alkyl, or a substituted orunsubstituted C1-C6haloalkyl.

In some embodiments, R350a is hydrogen or a substituted or unsubstitutedC₁-C₆alkyl. In yet other embodiments, R350a is hydrogen or a C1-C6alkyl.In yet other embodiments, R350a is hydrogen.

In some other embodiments, X250a is a substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted orunsubstituted C2-C6alkenyl, substituted or unsubstitutedC2-C6haloalkenyl, substituted or unsubstituted C2-C6alkynyl, orsubstituted or unsubstituted C2-C6haloalkynyl; and n is 1. In otherembodiments, X250a is a substituted or unsubstituted C1-C6alkyl, or asubstituted or unsubstituted C2-C6alkenyl.

In some embodiments, compounds provided herein have a structure selectedfrom among:

In certain embodiments, R100 is halogen, or an optionally substitutedgroup selected from among C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,phenyl, C1-C4alkyl(phenyl), C3-C8cycloalkyl,C1-C4alkyl(C3-C8cycloalkyl), C2-C8heterocycloalkyl,C1-C4alkyl(C2-C8heterocycloalkyl), heteroaryl, andC1-C4alkyl(heteroaryl); R200 is an optionally substituted group selectedfrom among C2-C10acyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl,C1-C4alkyl(C3-C6cycloalkyl), aryl, heteroaryl, heteroaralkyl,C1-C6alkylsulfonyl, C2-C6alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C1-C10alkoxycarbonyl, aminosulfonyl,C1-C6alkylaminosulfonyl, and di(C1-C6alkyl)aminosulfonyl.

In some embodiments, R350a is hydrogen; Y250 is a bond, —C(═O)—,—NHC(═O)—, —C(═O)NH—.

In other embodiments, L is selected from among:

C₁-C₄ alkyl,

In yet other embodiments, L is selected from among:

C₁-C₄ alkyl,

In one embodiment, compounds provided herein have a structure of Formula(IIIc). In other embodiments, compounds provided herein have a structureof Formula (IIIa). In yet other embodiments, compounds provided hereinhave a structure of Formula (IIIb).

In some embodiments, L is C₁-C₄ alkyl or

and R200 is an optionally substituted group selected from amongC2-C10acyl, aryl, heteroaryl, heteroaralkyl, C₁-C₆alkylsulfonyl,C₂-C₆alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In other embodiments, R²⁰⁰ is an optionally substituted group selectedfrom among C₂-C₁₀acyl, aryl, heteroaryl, heteroaralkyl,C₁-C₆alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In one aspect, L is selected from among C₁-C₄ alkyl,

R¹⁰⁰ is an optionally substituted group selected from among C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl, C₁-C₄alkyl(phenyl), C₃-C₈cycloalkyl,C₁-C₄alkyl(C₃-C₈cycloalkyl), C₂-C₈heterocycloalkyl,C₁-C₄alkyl(C₂-C₈heterocycloalkyl), heteroaryl, andC₁-C₄alkyl(heteroaryl); R²⁰⁰ is an optionally substituted group selectedfrom among C₂-C₁₀acyl, aryl, heteroaryl, hetero aralkyl,C₁-C₆alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁-C₁₀alkoxycarbonyl, aminosulfonyl, C₁-C₆alkylaminosulfonyl, anddi(C₁-C₆alkyl)aminosulfonyl.

In some embodiments, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylenesubstituted at the 2 position with

and substituted at the 6 position with

In yet other embodiments, Y250 is a bond, —O—, —S(═O)—, —S(═O)2-,—C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—,—NHSO2-, —SO2NH—, —NHC(═O)O—, or —OC(═O)NH—; E is O; and R350a ishydrogen, or a substituted or unsubstituted C1-C6alkyl.

In certain embodiments, X250a is a substituted or unsubstitutedC1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted orunsubstituted C2-C6alkenyl, substituted or unsubstitutedC2-C6haloalkenyl, substituted or unsubstituted C2-C6alkynyl, orsubstituted or unsubstituted C2-C6haloalkynyl; and n is 1.

In some embodiments, R100 is halogen, or an optionally substituted groupselected from among C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl,C1-C4alkyl(phenyl), C3-C8cycloalkyl, C1-C4alkyl(C3-C8cycloalkyl),C2-C8heterocycloalkyl, C1-C4alkyl(C2-C8heterocycloalkyl), heteroaryl,and C1-C4alkyl(heteroaryl); R²⁰⁰ is an optionally substituted groupselected from among C2-C10acyl, C2-C6alkenyl, C2-C6alkynyl,C3-C6cycloalkyl, C1-C4alkyl(C3-C6cycloalkyl), aryl, heteroaryl,heteroaralkyl, C1-C6alkylsulfonyl, C2-C6alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C1-C10alkoxycarbonyl, aminosulfonyl,C1-C6alkylaminosulfonyl, and di(C1-C6alkyl)aminosulfonyl.

In other embodiments, R^(350a) is hydrogen; Y²⁵⁰ is —C(═O)—; andX^(250a) is a substituted or unsubstituted C₁-C₆alkyl.

In certain embodiments, L is

In some embodiments, compounds provided herein have a structure ofFormula (Mb). In other embodiments compounds provided herein have astructure of Formula (IIIa). In yet other embodiments, compoundsprovided herein have a structure of Formula (IIIc).

In another embodiment, provided herein are compounds of Formula (IV):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene;    -   R^(d) is —OH, or —NH—C(O)—R^(e);    -   R^(c) is H or C₁-C₄alkyl, halogen, or C₁-C₄haloalkyl;    -   R^(e) is a substituted or unsubstituted group selected from        among C₁-C₆ alkyl, aryl, or heteroaryl; and    -   pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,substituted at the 2 position with

and substituted at the 7 position with

In certain embodiments, Rc is H; and Re is a substituted orunsubstituted group selected from among aryl, and heteroaryl. In otherembodiments, Re is a substituted or unsubstituted group selected fromamong phenyl, and heteroaryl containing 1 or 2 N atoms.

In another embodiment, provided herein are compounds of Formula (V):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or        1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;    -   L is —X^(250a)—Y²⁵⁰—X^(250b)— or —X^(250b)—Y²⁵⁰—X^(250a)—,        wherein,        -   X^(250a) is a bond, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   Y²⁵⁰ is a bond, —O—, —S(═O)—, —S(═O)₂—, —C(═O)—, —NR⁴⁵—,            —NH—, —NHC(═O)—, —NR⁴⁵C(═O)—, —NR⁴⁵C(═O)NR⁴⁵—, —C(═O)NH—,            —C(═O)NR⁴⁵—, —OC(═O)—, —C(═O)O—, —NHSO₂—, —NR⁴⁵SO₂—,            —SO₂NH—, —SO₂NR⁴⁵—, —C(R⁴⁵)═NO—, —CH═NO—, —ON═CH—,            heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR⁴⁵C(═O)O—, or            —OC(═O)NR⁴⁵—;        -   X^(250b) is a bond, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₁-C₆haloalkyl, substituted or            unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted            C₅-C₈cycloalkenyl, substituted or unsubstituted            C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆haloalkenyl,            substituted or unsubstituted C₂-C₆alkynyl, or substituted or            unsubstituted C₂-C₆haloalkynyl;        -   where each R⁴⁵ is independently selected from among            hydrogen, substituted or unsubstituted C₁-C₆alkyl,            substituted or unsubstituted C₃-C₈cycloalkyl, substituted or            unsubstituted C₂-C₆alkenyl, substituted or unsubstituted            C₂-C₆alkynyl;    -   R^(e) is a substituted or unsubstituted group selected from        among C₁-C₆ alkyl, aryl, and heteroaryl;    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In certain embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In other embodiments, Y250 is a bond; and R350a is hydrogen, asubstituted or unsubstituted C1-C6alkyl, a substituted or unsubstitutedC1-C6haloalkyl.

In one aspect, X250a is a bond; and X250b is a bond.

In another aspect, T is1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 6 position with

In some embodiments, X250a is a bond, substituted or unsubstitutedC1-C6alkyl; Y250 is a bond, —O—, —C(═O)—, —NH—, —NHC(═O)—, —NR45C(═O)—,—NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHC(═O)O—, or —OC(═O)NH—;and X250b is a bond, substituted or unsubstituted C₁-C₆alkyl, orsubstituted or unsubstituted C₁-C₆haloalkyl.

In some embodiments, Re is a substituted or unsubstituted group selectedfrom among C1-C6 alkyl, phenyl, and heteroaryl containing 1 or 2 Natoms.

In some embodiments, R350a is hydrogen, a substituted or unsubstitutedC1-C6alkyl, a substituted or unsubstituted C1-C6haloalkyl.

In other embodiments, Y250 is a bond, —NHC(═O)—, —C(═O)NH—, —OC(═O)—, or—C(═O)O—.

In another aspect, provided herein are compounds of Formula (VI):

wherein:

-   -   R^(a) and R^(b) are each independently selected from among H,        halogen, CN, NO₂, C₁-C₄alkyl, C₁-C₄haloalkyl, and C₁-C₄alkoxy;    -   T is        1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene,        or        1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;    -   L is a substituted or unsubstituted C₁-C₆alkyl, substituted or        unsubstituted C₁-C₆haloalkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted C₃-C₈cycloalkyl,        substituted or unsubstituted C₅-C₈cycloalkenyl, substituted or        unsubstituted C₂-C₆alkenyl, substituted or unsubstituted        C₂-C₆heteroalkenyl, substituted or unsubstituted        C₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, or        substituted or unsubstituted C₂-C₆haloalkynyl;    -   R^(f) is a substituted or unsubstituted C₂-C₆alkynyl;    -   R^(g) is H, or an optionally substituted group selected from        among C₂-C₁₀acyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        C₁-C₄alkyl(C₃-C₆cycloalkyl), aryl, heteroaryl, hetero aralkyl,        C₁-C₆alkylsulfonyl, C₂-C₆alkenylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁-C₁₀alkoxycarbonyl, aminosulfonyl,        C₁-C₆alkylaminosulfonyl, and di(C₁-C₆alkyl)aminosulfonyl;    -   R^(350a) is hydrogen, a substituted or unsubstituted C₁-C₆alkyl,        a substituted or unsubstituted C₂-C₆alkenyl, a substituted or        unsubstituted C₂-C₆alkynyl, a substituted or unsubstituted        C₁-C₆haloalkyl, a substituted or unsubstituted C₂-C₆haloalkenyl,        or a substituted or unsubstituted C₂-C₆haloalkynyl; and        pharmaceutically active metabolites, pharmaceutically acceptable        solvates, pharmaceutically acceptable salts, or pharmaceutically        acceptable prodrugs thereof.

In some embodiments, T is1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylenesubstituted at the 2 position with

and substituted at the 7 position with

In some embodiments, L is a substituted or unsubstituted C1-C6alkyl,substituted or unsubstituted C1-C6haloalkyl, substituted orunsubstituted C1-C6heteroalkyl, substituted or unsubstitutedC2-C6alkenyl, or substituted or unsubstituted C2-C6heteroalkenyl; andR350a is hydrogen, a substituted or unsubstituted C1-C6alkyl. In otherembodiments, L is a substituted or unsubstituted C1-C6alkyl, substitutedor unsubstituted C1-C6heteroalkyl, substituted or unsubstitutedC2-C6alkenyl, or substituted or unsubstituted C2-C6heteroalkenyl.

In other embodiments, Rg is H, or an optionally substituted groupselected from among C2-C10acyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,C1-C6alkylsulfonyl, C2-C6alkenylsulfonyl, arylsulfonyl,heteroarylsulfonyl, or C1-C10 alkoxycarbonyl.

In some embodiments, L is a substituted or unsubstituted C1-C6alkyl, orsubstituted or unsubstituted C2-C6alkenyl; and Rg is H, or an optionallysubstituted C1-C6alkyl.

In some embodiments, L is selected from among a substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆haloalkyl,substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstitutedC₂-C₆haloalkenyl, substituted or unsubstituted C₂-C₆alkynyl, orsubstituted or unsubstituted C₂-C₆haloalkynyl,

In other embodiments, L is selected from among a substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₂-C₆alkenyl,

In yet other embodiments, L is selected from among a substituted orunsubstituted C₁-C6alkyl, substituted or unsubstituted C₂-C₆alkenyl,

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Further embodiments of compounds of Formula (Ia), Formula (Ib), Formula(Ic), Formula (II), Formula (III), Formula (IIIa), Formula (Mb), Formula(IIIc), Formula (IV), Formula (V), and Formula (VI), include, but arenot limited to, compounds shown in Tables 1-6.

TABLE 1

Cmpd. No. Q X^(b) Y X^(a) R^(b) 1

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 2

bond bond —CH₂CH═CH— 2,6-dichlorophenyl 3

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 4

bond bond —CH₂CH═CH— 3-fluoro-6-methylphenyl 5

bond bond —CH₂CH═CH— 2,6-dichlorophenyl 6

bond bond —CH₂CH═CH— 2,4-dichloro-6- methylphenyl 7

bond —C(O)— —CH═CH— 3-fluoro-6-methylphenyl 8

bond bond —CH₂CH₂CH₂— 2,4-dichloro-6- methylphenyl 9

bond bond —CH₂CH₂CH₂— 4-fluoro-2-methylphenyl 10

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 11

bond bond —CH₂CH═CH— 3-fluoro-6-methylphenyl 12

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 13

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 14

bond bond —CH₂CH═CH— 4-fluoro-2-methylphenyl 15

bond —C(O)NH— —CH₂CH═CH— 4-fluoro-2-methylphenyl 16

bond —C(O)NH— —CH₂CH═CH— 4-fluoro-2-methylphenyl 17

bond —C(O)NH— —CH₂CH═CH— 4-fluoro-2-methylphenyl

Compounds in Table 1 are named:

-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 1);-   2-(2,6-dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 2);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 3);-   2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 4);-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 5);-   2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 6);-   2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-{2-[(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-carbonyl]ethenyl}-1,8-dihydro-imidazo[4,5-h]    isoquinolin-9-one (Compound 7);-   2-(2,4-dichloro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]    isoquinolin-9-one (Compound 8);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propyl]-1,8-dihydro-imidazo[4,5-h]    isoquinolin-9-one (Compound 9);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-fluorophenyl)-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]    isoquinolin-9-one (Compound 10);-   2-(3-fluoro-6-methylphenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-(4-methoxyphenyl)-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]    isoquinolin-9-one (Compound 11);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 12);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ⁵-[1,4-]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 13);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 14);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-methyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 15);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-trans-phenyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 16); and-   2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-oxo-1-cis-phenyl-1λ⁵-phosphinan-4-yl)-carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 17).

TABLE 2

Cmpd. No. Q X^(b) Y X^(a) R^(b) 18 N-phenylpiperazin-1-yl bond bond—CH₂CH═CH— 2,6-dichlorophenyl 19 N-phenylpiperazin-1-yl bond bond—CH₂CH═CH— 4-fluoro-2-methyl- phenyl 20N-(4-chlorophenyl)-piperazin-1-yl bond bond —CH₂CH═CH—4-fluoro-2-methyl- phenyl 21 N-(methylcarbonyl)-piperazin-1-yl bond bond—CH₂CH═CH— 4-fluoro-2-methyl- phenyl 22N-(phenylcarbonyl)-piperazin-1-yl bond bond —CH₂CH═CH—4-fluoro-2-methyl- phenyl 23 N-(pyridin-4-yl)-piperazin-1-yl bond bond—CH₂CH═CH— 4-fluoro-2-methyl- phenyl 24N-(methylsulfonyl)-piperazin-1-yl bond bond —CH₂CH═CH—4-fluoro-2-methyl- phenyl 25 N-(methylsulfonyl)-piperazin-1-yl bond bond—CH₂CH═CH— 3-fluoro-2-methyl- phenyl 26 N-(pyridin-2-yl)-piperazin-1-ylbond bond —CH₂CH═CH— 4-fluoro-2-methyl- phenyl 27N-(pyrimidin-2-yl)-piperazin-1-yl bond bond —CH₂CH═CH—4-fluoro-2-methyl- phenyl 28 N-(2,6-dichlorophenylmethyl)- bond bond—CH₂CH═CH— 4-fluoro-2-methyl- piperazin-1-yl phenyl 29N-(phenylsulfonyl)-piperazin-1-yl bond bond —CH₂CH═CH—4-fluoro-2-methyl- phenyl 30 N-(4-fluorophenyl)-piperazin-1-yl bond bond—CH₂CH═CH— 4-fluoro-2-methyl- phenyl 31 N-(tert-butyloxycarbonyl)- bondbond —CH₂CH═CH— 4-fluoro-2-methyl- piperazin-1-yl phenyl 32N-(N,N-dimethylaminosulfonyl)- bond bond —CH₂CH═CH— 4-fluoro-2-methyl-piperazin-1-yl phenyl 33 N-(ethylcarbonyl)-piperazin-1-yl bond bond—CH₂CH═CH— 4-fluoro-2-methyl- phenyl 34N-(isopropylsulfonyl)-piperazin-1- bond bond —CH₂CH═CH—4-fluoro-2-methyl- yl phenyl 35 N-(ethylsulfonyl)-piperazin-1-yl bondbond —CH₂CH═CH— 4-fluoro-2-methyl- phenyl 36N-(isopropylcarbonyl)-piperazin-1- bond bond —CH₂CH═CH—4-fluoro-2-methyl- yl phenyl 52 N-(methylsulfonyl)-piperazin-1-yl bondbond —CH₂CH═CH— 5-fluoro-2-methyl- phenyl

Compounds in Table 2 are named:

-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 18);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 19);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-chlorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 20);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 21);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 22);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-4-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 23);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 24);-   2-(3-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 25);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyridin-2-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 26);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(pyrimidin-2-yl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 27);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(2,6-dichlorophenylmethyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 28);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-phenylsulfonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 29);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(4-fluorophenyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 30);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-tert-butyloxycarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 31);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N—(N,N-dimethylaminosulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 32);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-ethylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 33);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(isopropylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 34);-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-(ethylsulfonyl)-piperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 35); and-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-isopropylcarbonylpiperazin-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 36).

TABLE 3

Cmpd. No. Q X^(b) Y X^(a) R^(b) 37 phenyl bond —S(O)₂— —CH═CH— 2,6-dichloro- phenyl 38 phenyl bond —C(O)O— prop-2-en-1,1- 2,6- diyldichloro- phenyl 39 phenyl bond —C(O)O— 2,2- 2,6- difluorobutyn-dichloro- 1,1-diyl phenyl 40 N-phenyl- bond bond —CF₂CH(OH)— 2,6-methyl- dichloro- [1,2,3] phenyl triazol- 4-yl 41 phenyl bond bond—C≡CCH(OH)— 2,6- dichloro- phenyl

Compounds in Table 3 are named:

-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2-(phenylsulfonyl)-ethenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 37);-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-prop-2-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 38);-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[1-(phenylcarbonyloxy)-2,2-difluorobutynyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 39);-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[2,2-difluoro-1-hydroxy-2-(N-phenylmethyl-[1,2,3]triazol-4-yl)-ethyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 40);-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-(1-hydroxy-3-phenylprop-2-yn-1-yl)-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 41);

TABLE 4

Cmpd. No. R^(f) R^(g) L R^(b) 42 prop-1-yn-3-yl methyl —CH₂CH═CH—2,6-dichloro- phenyl 43 prop-1-yn-3-yl methyl —CH₂CH═CH— 4-fluoro-2-methylphenyl

Compounds in Table 4 are named:

-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 42); and-   2-(4-fluoro-2-methylphenylamino)-1,6-dimethyl-7-[3-(N-methyl-N-(prop-2-ynyl)amino)prop-1-enyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 43);

TABLE 5

Cmpd. No. R^(e) R^(b) 44 —OH 2,6-dichlorophenyl 45 phenylamido2,6-dichlorophenyl 46 4-(N,N-dimethylamino)-phenylamido2,6-dichlorophenyl 47 (pyridin-2-yl)amido 2,6-dichlorophenyl 48(pyridin-3-yl)amido 2,6-dichlorophenyl 49 2-methoxyphenylamido2,6-dichlorophenyl

Compounds in Table 5 are named:

-   2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde    oxime (Compound 44); benzoic acid    [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide    (Compound 45);-   4-(N,N-dimethylamino)-benzoic acid    [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide    (Compound 46);-   pyridine-2-carboxylic acid    [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide    (Compound 47);-   pyridine-3-carboxylic acid    [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide    (Compound 48); and-   2-methoxy-benzoic acid    [2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-ylmethylene]-hydrazide    (Compound 49).

TABLE 6

Cmpd. No. Q X^(b) Y X^(a) R^(b) 50

bond —C(O)— —CH₂— 4-fluoro-2- methylphenyl 51

butan-1,1-diyl —NHC(O)— —CH₂— 4-fluoro-2-methyl- phenyl

Compounds in Table 6 are named:

-   2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{2-[4-(4-fluorophenyl)-4-oxo-4λ^(5[)1,4]azaphosphinan-1-yl]-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 50); and-   (S)-2-(4-fluoro-2-methylphenylamino)-1,7-dimethyl-6-{N-[1-(phenylsulfonyl)hex-1-en-3-yl]-amino-2-oxoethyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one    (Compound 51).

In one embodiment, provided herein is an optionally substituted ringsystem, where one ring member is —P(=E)(R¹⁰⁰)—, of structure 34:

wherein:

-   -   E is oxygen;    -   R¹⁰⁰ is defined herein; and    -   n is 1, 2, or 3.

In another embodiment, provided herein is an optionally substituted ringsystem where one ring member is —P(=E)(R¹⁰⁰)—, of structure 9:

wherein

-   -   E is oxygen;    -   R¹⁰⁰ is defined herein;    -   and n is 1, 2, or 3.

In another embodiment, provided herein is a process of preparing acompound of Formula (Ia), Formula (Ib) or Formula (Ic), which includes:

(a) reacting an optionally substituted ring system of structure 34:

-   -   (a) with a carboxylic acid (or a salt thereof or an activated        acid derivative thereof) of structure I(i):

wherein:

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), —SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;            -   where each R⁷ is independently selected from among                hydrogen, optionally substituted alkyl, optionally                substituted alkenyl, optionally substituted alkynyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and                heterocycloaklalkyl;            -   A¹ is alkylene, alkenylene, or alkynylene;            -   R^(8a) is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or hetero cycloalkylalkyl;            -   R^(8b) is hydrogen or R^(8a);            -   R⁶ is optionally substituted alkyl, cycloalkyl,                cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl;            -   R³³ is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or hetero cycloalkylalkyl; and            -   where alkyl, alkenyl, alkynyl, and alkylene, either                alone or as part of another group within R^(1a), are                independently optionally substituted with one, two,                three, four, or five halo;        -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            heteroaryl, heteroaralkyl, heterocycloalkyl, or            heterocycloalkylalkyl; or        -   R^(1a) and R^(1b) together with the nitrogen to which they            are attached form heterocycloalkyl or heteroaryl;        -   R^(1c) and R^(1d) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl, acyl,            cycloalkyl, cycloalkylalkyl, heterocycloalkyl,            heterocycloalkylalkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, or -(A¹⁸)-C(O)NR^(50a)R^(50b);            -   A¹⁸ is alkylene, alkenylene, or alkynylene; and            -   R^(50a) and R^(50b) are independently hydrogen,                optionally substituted alkyl, aryl, aralkyl, heteroaryl,                heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl); and        -   where alkyl, alkenyl, and alkylene either alone or as part            of another group within R^(1a), R^(1b), R^(1c) and R^(1d),            are independently optionally substituted with one, two,            three, four, or five halo;    -   R^(2a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy,        alkoxy, alkenyloxy, optionally substituted phenyl, cyano,        optionally substituted phenyl, heteroaryl, —NR^(14a)R^(14b),        -(A¹)-NR^(12a)R^(12b), —NR^(13a)C(O)R^(13b),        -(A¹)-NR^(13a)C(O)R^(13b), —C(O)NR^(14a)R^(14b), or        -(A¹)-C(O)NR^(12a)R^(12b); and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(2a), are independently            optionally substituted with one, two, three, four, or five            halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;    -   R³ is hydrogen, halo, acyl, acylamino, acyloxy, alkyl, alkenyl,        alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        -(A⁵)-S(O)₀₋₂R⁵³, -(A⁵)-N(R⁵⁴)₂, -(A⁵)-OR⁵⁵, -(A⁵)-OC(O)R⁵³,        -(A⁵)-C(O)R⁵³, (A⁵)-C(O)OR⁵⁵, -(A⁵)-C(O)N(R⁵⁴)₂,        -(A⁵)-NR⁵⁴C(O)R⁵³, -(A⁵)-S(O)₂N(R⁵⁴)₂, -(A⁵)-NR⁵⁴S(O)₂R⁵³,        -(A⁵)-OC(O)N(R⁵⁴)₂, -(A⁵)-NR⁵⁴C(O)OR⁵⁵, or        -(A⁵)-NR⁵⁴C(O)N(R⁵⁴)₂;        -   A⁵ is a bond, alkylene, alkenylene, or alkynylene;        -   R⁵³ is optionally substituted alkyl, optionally substituted            alkenyl, optionally substituted alkynyl, aryl, aralkyl,            heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl;        -   R⁵⁴ is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, aryl, aralkyl, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,            heteroaryl, or heteroaralkyl;        -   R⁵⁵ is hydrogen or R⁵³; and        -   where alkyl, alkenyl, alkynyl, alkylene, alkenylene, and            alkynylene, either alone or as part of another group within            R³, are independently optionally substituted with one, two,            three, four, or five halo;            to give a compound of formula I(b):

or

-   -   (b) with an intermediate of formula I(h):

or a salt thereof, where R′ is a leaving group such as halo;

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), -SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;            -   where each R⁷ is independently selected from among                hydrogen, optionally substituted alkyl, optionally                substituted alkenyl, optionally substituted alkynyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and                heterocycloaklalkyl;            -   A¹ is alkylene, alkenylene, or alkynylene;            -   R^(8a) is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl;            -   R^(8b) is hydrogen or R^(8a);            -   R⁶ is optionally substituted alkyl, cycloalkyl,                cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl;            -   R³³ is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl; and            -   where alkyl, alkenyl, alkynyl, and alkylene, either                alone or as part of another group within R^(1a), are                independently optionally substituted with one, two,                three, four, or five halo;        -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            heteroaryl, heteroaralkyl, heterocycloalkyl, or            heterocycloalkylalkyl; or        -   R^(1a) and R^(1b) together with the nitrogen to which they            are attached form heterocycloalkyl or heteroaryl;        -   R^(1c) and R^(1d) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl, acyl,            cycloalkyl, cycloalkylalkyl, heterocycloalkyl,            heterocycloalkylalkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, or -(A¹⁸)-C(O)NR^(50a)R^(50b);            -   A¹⁸ is alkylene, alkenylene, or alkynylene; and            -   R^(50a) and R^(50b) are independently hydrogen,                optionally substituted alkyl, aryl, aralkyl, heteroaryl,                hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl); and        -   where alkyl, alkenyl, and alkylene either alone or as part            of another group within R^(1a), R^(1b), R^(1c) and R^(1d),            are independently optionally substituted with one, two,            three, four, or five halo;        -   R^(150a) is R^(2a) and R^(150b) is R^(2b);        -   or R^(150a) is R^(2b) and R^(150b) is R^(2a).        -   R^(2a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, optionally substituted phenyl,            cyano, optionally substituted phenyl, heteroaryl,            —NR^(14a)R^(14b), -(A¹)-NR^(12a)R^(12b),            —NR^(13a)C(O)R^(13b), -(A¹)-NR^(13a)C(O)R^(13b),            —C(O)NR^(14a)R^(14b), or -(A¹)-C(O)NR^(12a)R^(12b); and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(2a), are independently            optionally substituted with one, two, three, four, or five            halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;        -   R^(2b) is —X^(2a)—Y²—X^(2b)-Q² where        -   X^(2a) is a bond, alkylene, alkenylene, or alkynylene where            the alkylene, alkenylene, and alkynylene are optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy;        -   Y² is a bond, —O—, —S(O)_(n1)— (where n1 is 0, 1, or 2),            —C(O)—, —NR⁴⁵—, —NR⁴⁵C(O)—, —NR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(═NR⁴⁵)NR⁴⁵—, —C(O)NR⁴⁵—, —OC(O)—, —C(O)O—,            —C(O)N(R⁴⁵)N═CR⁷⁴—, —NR⁴⁵SO₂—, —SO₂NR⁴⁵—, —C(R⁷⁴)(═NO)—,            —C(R⁷⁴)═NNR⁴⁵—, —C(R⁷⁴)═NNR⁴⁵C(O)—, —C(R⁷⁴)═NNR⁴⁵C(O)NR⁴⁵—,            —NR⁴⁵C(O)O—, or —OC(O)NR⁴⁵—;            -   where R⁴⁵ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, hydroxy, alkoxy, or alkenyloxy;            -   R⁷⁴ is hydrogen, optionally substituted alkyl,                optionally substituted alkenyl, or optionally                substituted alkynyl; and            -   where alkyl, alkenyl, and alkynyl, either alone or as                part of another group within Y², are independently                optionally substituted with one, two, three, four, or                five halo;        -   X^(2b) is a bond; and        -   Q² is hydrogen, cyano, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl,            cycloalkyl, heterocycloalkyl, or heteroaryl;            to give a compound of Formula I(e):

or

-   -   (b) reacting an intermediate of Formula 9:

or a salt thereof or an activated acid derivative thereof, where n is 1,2 or 3 and R¹⁰⁰ is as defined in (a) with an intermediate of formulaI(g):

or a salt thereof,where

-   -   J is —O—, —S—, or —NR⁵—; where R⁵ is hydrogen, hydroxy, alkoxy,        alkenyloxy, acyl, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl,        alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, alkylsulfonyl, alkylaminosulfonyl, or        dialkylaminosulfonyl; and where alkyl, alkenyl, alkynyl, and        alkylene, either alone or as part of another group within J, are        independently optionally substituted with one, two, three, four,        or five halo;    -   Y^(a) is —NR^(1a)R^(1b), —OR^(1c), or —SR^(1d) where        -   R^(1a) is hydrogen, optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            hydroxy, alkoxy, alkenyloxy, acyl, —C(O)N(R⁷)₂,            -(A¹)-C(O)NR^(8a)R^(8b), —SO₂R⁶, -(A¹)-SO₂R⁶, —SO₂N(R⁷)₂,            -(A¹)-SO₂N(R⁷)₂, —C(O)OR⁶, -(A¹)-C(O)OR³³, cycloalkyl,            cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl;            -   where each R⁷ is independently selected from among                hydrogen, optionally substituted alkyl, optionally                substituted alkenyl, optionally substituted alkynyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and                heterocycloaklalkyl;            -   A¹ is alkylene, alkenylene, or alkynylene;            -   R^(8a) is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl;            -   R^(8b) is hydrogen or R^(8a);            -   R⁶ is optionally substituted alkyl, cycloalkyl,                cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl;            -   R³³ is substituted alkyl, substituted alkenyl,                substituted alkynyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl; and            -   where alkyl, alkenyl, alkynyl, and alkylene, either                alone or as part of another group within R^(1a), are                independently optionally substituted with one, two,                three, four, or five halo;        -   R^(1b) is aryl, aralkyl, cycloalkyl, cycloalkylalkyl,            heteroaryl, heteroaralkyl, heterocycloalkyl, or            heterocycloalkylalkyl; or        -   R^(1a) and R^(1b) together with the nitrogen to which they            are attached form heterocycloalkyl or heteroaryl;        -   R^(1c) and R^(1d) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl, acyl,            cycloalkyl, cycloalkylalkyl, heterocycloalkyl,            heterocycloalkylalkyl, aryl, aralkyl, heteroaryl,            heteroaralkyl, or -(A¹⁸)-C(O)NR^(50a)R^(50b);            -   A¹⁸ is alkylene, alkenylene, or alkynylene; and            -   R^(50a) and R^(50b) are independently hydrogen,                optionally substituted alkyl, aryl, aralkyl, heteroaryl,                hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl); and        -   where alkyl, alkenyl, and alkylene either alone or as part            of another group within R^(1a), R^(1b), R^(1c) and R^(1d),            are independently optionally substituted with one, two,            three, four, or five halo;    -   R^(2a) is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, hydroxy,        alkoxy, alkenyloxy, optionally substituted phenyl, cyano,        optionally substituted phenyl, heteroaryl, —NR^(14a)R^(14b),        -(A¹)NR^(12a)R^(12b), —NR^(13a)C(O)R^(13b),        -(A¹)-NR^(13a)C(O)R^(13b), —C(O)NR^(14a)R^(14b), or        -(A¹)-C(O)NR^(12a)R^(12b); and        -   where alkyl, alkenyl, alkynyl, and alkylene, either alone or            as part of another group within R^(2a), are independently            optionally substituted with one, two, three, four, or five            halo;        -   R^(12a) is substituted alkyl, substituted alkenyl,            substituted alkynyl, hydroxy, cyanoalkyl, alkoxy, or            alkenyloxy; and R^(12b) is hydrogen or R^(12a);        -   R^(14a) and R^(14b) are independently hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, hydroxy, cyanoalkyl, alkoxy,            or alkenyloxy;        -   R^(13a) is hydrogen, optionally substituted alkyl,            optionally substituted alkenyl, optionally substituted            alkynyl, hydroxy, cyanoalkyl, alkoxy, alkenyloxy,            cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl and            R^(13b) is optionally substituted alkyl, optionally            substituted alkenyl, optionally substituted alkynyl,            cyanoalkyl, alkoxy, alkenyloxy, or cycloalkyl;    -   R³ is —X^(3a)—Y³—X^(3b)-Q⁴ where        -   X^(3a) is a bond, alkylene, alkenylene, or alkynylene where            alkylene, alkenylene, and alkynylene are independently            optionally substituted with one, two, three, four, or five            halo or one or two hydroxy,        -   Y³ is —C(O)—, or —NR⁵¹— where R⁵¹ is hydrogen, optionally            substituted alkyl, optionally substituted alkenyl,            optionally substituted alkynyl, cycloalkyl, cycloalkylalkyl,            heterocycloalkyl, or heterocycloalkylalkyl and where alkyl,            alkenyl, and alkynyl, either alone or as part of another            group within Y³, are independently optionally substituted            with one, two, three, four, or five halo,        -   X^(3b) is a bond, alkylene, alkenylene, alkynylene,            cycloalkylene, or heterocycloalkylene where alkylene,            alkenylene, and alkynylene are independently optionally            substituted with one, two, three, four, or five halo or one            or two hydroxy, and        -   Q⁴ is Z where Z is —P(=E)(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(Y^(10a)R^(60a))(Y^(10b)R^(60b)),            —P(=E)(Y^(10e)R^(60a))(Z¹⁰R⁶¹), or an optionally substituted            ring system where one ring member is —P(=E)(R¹⁰⁰)—;            -   E is oxygen or sulfur;            -   Y^(10a) and Y^(10b) are independently a single bond,                —O—, —S—, or —NR^(62a)— where R^(62a) is hydrogen,                hydroxy, alkoxy, alkenyloxy, optionally substituted                alkyl, optionally substituted alkenyl, or optionally                substituted alkynyl;            -   R^(60a) and R^(60b) are independently hydrogen,                optionally substituted alkyl, optionally substituted                alkenyl, optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, hetero aralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b), respectively, is —O—, —S—, or —NR^(62a)—;            -   R^(60a) and R^(60b) are independently optionally                substituted alkyl, optionally substituted alkenyl,                optionally substituted alkynyl, aryl, aralkyl,                heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, or heterocycloalkylalkyl when Y^(10a)                or Y^(10b), respectively, is a single bond;            -   Y^(10e) is —O—, —S—, or —NR^(62a)—;            -   Z¹⁰ is alkylene, alkenylene, alkynylene, —O—, —S—, or                —NR^(62a)—;            -   R⁶¹ is hydrogen, acyl, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,                cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or                heterocycloalkylalkyl; or            -   R⁶¹ is —P(E)(Y^(10a)R^(60a))(Y^(10b)R^(60b));            -   R¹⁰⁰ is a single bond from the phosphorous atom to                X^(1b), or R¹⁰⁰ is halo, optionally substituted alkyl,                optionally substituted alkenyl, optionally substituted                alkynyl, optionally substituted phenyl, optionally                substituted phenylalkyl, cycloalkyl, cycloalkylalkyl,                heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,                heteroaralkyl, —OR¹⁰¹, or —NR^(102a)R^(102b); and                -   where the alkyl, alkenyl, and alkynyl within R¹⁰⁰,                    either alone or as part of another substituent, are                    independently optionally substituted with one, two,                    three, four, or five halo;                -   R¹⁰¹ is hydrogen, optionally substituted alkyl,                    optionally substituted alkenyl, or optionally                    substituted alkynyl;                -   R^(102a) and R^(102b) are independently hydrogen,                    optionally substituted alkyl, optionally substituted                    alkenyl, optionally substituted alkynyl, aryl,                    aralkyl, heteroaryl, hetero aralkyl, cycloalkyl,                    cycloalkylalkyl, heterocycloalkyl, or                    heterocycloalkylalkyl;                -   X^(2a) is a bond, alkylene, alkenylene, or                    alkynylene where the alkylene, alkenylene, and                    alkynylene are optionally substituted with one, two,                    three, four, or five halo or one or two hydroxy;                -   and Y′ is —OH, —NHR¹⁸, or —C(O)NHR²² where R¹⁸ and                    R²² are independently hydrogen, optionally                    substituted alkyl, optionally substituted alkenyl,                    optionally substituted alkynyl, hydroxy, alkoxy, or                    alkenyloxy;                    to give a compound of Formula I(f):

where Y″ is —O—, NR¹⁸—, or NR²²—;and

-   -   (a) optionally separating individual isomers of the compounds;    -   (b) optionally forming an acid addition salt of the product        formed in Step (a) or (b) above;    -   (c) optionally forming a free base of the product formed in        Step (a) or (b) above;    -   (d) optionally modifying any of the J, Y^(a), and groups in the        product formed in Step (a), (b), (c), (d), or (e) above.

Preparation of Compounds

Compounds provided herein, which inhibit the activity of tyrosinekinases, such as Bruton's tyrosine kinase (Btk), may be synthesizedusing standard synthetic techniques known to those of skill in the artor using methods known in the art in combination with methods describedherein. As a further guide the following synthetic methods may also beutilized.

The reactions can be employed in a linear sequence to provide thecompounds described herein or they may be used to synthesize fragmentswhich are subsequently joined by the methods described herein and/orknown in the art.

Use of Protecting Groups

The term “protecting group” refers to chemical moieties that block someor all reactive moieties and prevent such groups from participating inchemical reactions until the protective group is removed. It ispreferred that each protective group be removable by a different means.Protective groups that are cleaved under totally disparate reactionconditions fulfill the requirement of differential removal. Protectivegroups can be removed by acid, base, and hydrogenolysis. Groups such astrityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labileand may be used to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and Fmoc groups, which are base labile. Carboxylicacid and hydroxy reactive moieties may be blocked with base labilegroups such as, without limitation, methyl, ethyl, and acetyl in thepresence of amines blocked with acid labile groups such as t-butylcarbamate or with carbamates that are both acid and base stable buthydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester derivatives asexemplified herein, or they may be blocked with oxidatively-removableprotective groups such as 2,4-dimethoxybenzyl, while co-existing aminogroups may be blocked with fluoride labile silyl carbamates. In oneembodiment, a compound containing both a carboxylic acid reactive moietyand a hydroxy reactive moiety may have one of the reactive moietiesblocked while the other reactive moiety is not blocked.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd0-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups are described in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y.,1999, which is incorporated herein by reference in its entirety.

Synthesis of Compounds

In certain embodiments, provided herein are methods of making andmethods of using tyrosine kinase inhibitor compounds described herein.In certain embodiments, compounds described herein can be synthesizedusing the following synthetic schemes. Compounds may be synthesizedusing methodologies analogous to those described below by the use ofappropriate alternative starting materials.

Described herein are compounds that inhibit the activity of tyrosinekinase(s), such as Btk, and processes for their preparation. Alsodescribed herein are pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically active metabolites andpharmaceutically acceptable prodrugs of such compounds. Pharmaceuticalcompositions that include at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, are provided.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg,Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001);Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17(John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989);Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). (all of which are incorporated by reference in their entirety).Other methods for the synthesis of compounds described herein may befound in International Patent Publication No. WO 01/25238, U.S. Pat. No.6,506,769, U.S. Pat. No. 6,770,639; Snow et al. Tetrahedron Letters, 43(2002) 7553-7556; Goldberg et al. J. Med. Chem. 2003, 46, 1337-1349;Snow et al. J. Med. Chem. 2002, 45, 3394-3405; and J. HeterocyclicChem., 1970, 7, 615. General methods for the preparation of compound asdisclosed herein may be derived from known reactions in the field, andthe reactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods may be utilized.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingobtaining physical properties and spectral data.

Compounds described herein may be prepared using the synthetic methodsdescribed herein as a single isomer or a mixture of isomers.

Ring systems where one ring member is a phosphine or phosphine oxide canbe prepared by following the procedure outlined in Scheme I. Treatmentof a halodialkoxyphosphine oxide, such as, for example,chlorodiethoxyphosphine oxide (structure 1), with an alkyl metal salt,such as for example, a grignard reagent, provide compounds of structure2. Treatment of phosphine oxides of structure 2 withbromotrimethylsilane, followed by oxalyl chloride, provides halophosphine oxides of structure 3. Compounds of structure 3 are alsocommercially available.

Compounds of structure 3 can also be prepared by reacting P(ORa)2(ORb)where Ra is methyl or ethyl and Rb is hydrogen, methyl or ethyl, e.g.trimethyl phosphite or diethyl phosphite, with R100X, where X ishalogen. Where R100 is an optionally substituted aryl or heteroaryl, thereaction is carried out in the presence of a metal catalyst, such as,for example, a palladium catalyst, such as, for example,tetrakis(triphenylphosphine)-palladium, in the presense of a base, suchas, for example, triethylamine.

Compounds of structure 3 are then treated with a vinyl metal salt, suchas, for example, vinylmagnesium bromide, to give compounds of structure4. Divinyl phosphine oxides of structure 4 are treated with a primaryamine, such as, for example, benzylamine or p-methoxybenzylamine, toprovide the cyclic amines of structure 5. Removal of the protectinggroup on the nitrogen, such as, by catalytic hydrogenation, providescyclic amines of structure 6.

Scheme II depicts the synthesis of cyclic phosphine oxides such asstructre 9. Reacting divinyl phosphine oxides of structure 4 with amalonate, such as, for example, dibenzylmalonate, in the presence of abase, such as, for example, potassium carbonate, providesheterocycloalkyls of structure 7. Compounds of structure 7 are thendeprotected under reducing conditions, such as, by treatment withhydrogen in the presence of a catalyst, such as, for example, palladiumon carbon in a suitable solvent such as, for example, ethanol, to yieldthe dicarboxylic acids of structure 8. Decarboxylation of dicarboxylicacids of structure 8 provides carboxylic acids of structure 9. In oneembodiment, 8 is decarboxylated under microwave conditions, such as, forexample, at a temperature of over about 200° C. In another embodiment, 8is decarboxylated under acidic conditions, such as, for example, byheating a solution of 8 in the presence of 1N HCl. Other methods ofdecarboxylating beta ketoacids are known in the art.

As shown in Scheme III, the synthesis of allylic acetates of structure21 begins by performing a selective SNAr reaction with2,6-dichloro-3-nitrobenzonitrile (10). Reaction of 10 with an amine,such as, for example, ammonia or an alkylamine, such as, for example,methylamine, provides structure 12. A subsequent SNAr reaction ofstructure 12 with an alkyl acetoacetate derivative provides structure14, which contains the necessary number of atoms to form theisoquinoline core. Reduction of the nitro moiety nitroaromatics ofstructure 14, is followed by formation of the benzimidazole by reactingdiamines of structure 15 with an isothiocyante, such as for example, anaryl isothiocyanate, in the presence of mercuric oxide (HgO) inrefluxing THF. Alternatively, diamines of structure 15 are treated witha isothiocyante and the intermediate thiourea is treated with anactivating agent, such as, for example, 1,3-dicyclohexylcarbodiimide(DCC), to provide benzimidazoles of structure 17.

The isoquinolone moiety is then formed by treatment of benzimidazoles ofstructure 17 with acid to polycycles of structure 18. The formation ofpolycycles of structure 18 involves hydrolysis of the nitrile followedby condensation with the ketone. Depending on the reaction conditionsused, isoquinolone formation may or may not involve decarboxylation ofthe ester moiety. For example, under mild acidic reaction conditions,such as in the treatment of benzimidazoles of structure 17 with sulfuricacid at room temperature, 18 is obtained, where R2a is —C(O)OEt. Inother embodiments, treatment of benzimidazoles of structure 17 withsulfuric acid, water and acetic acid at 100° C., provides 18, whichinvolves hydrolysis of the nitrile, condenstaion with the ketone, anddecarboxylation of the ester moiety in one step.

Treatment of structure 18 with selenium dioxide in an ethereal solvent,such as, for example, dioxane, results in selective oxidation at the C-7methyl to provide aldehydes of structure 19. Aldehydes of structure 19are then treated with a vinyl metal salt, such as, for example,vinylmagnesium bromide to provide 20. Treatment of 20 with an activatedcarboxylic acid, such as, for example, acetic anhydride, providesallyllic acetates of structure 21.

Scheme IV depicts the synthesis of benzothiazoles. A S_(N)Ar reaction of2-chloro-5-nitrobenzonitrile (22) with an alkyl acetoacetate derivativeprovides structure 23. Isoquinolones of structure 24 are formed bytreatment of structure 23 with acid. Reduction of the nitro moiety ofstructure 24 is followed by treatment of amines of structure 25 with anisothiocyante to provide a thiourea intermediate (26). Reaction of thethiourea intermediate of structure 26 under cyclizing conditions, suchas in the presence of bromine in a suitable solvent, such as, forexample, chloroform, provides the benzothiazole. Furtherfunctionalization and manipulation of the benzothiazole is then carriedout as described herein or known in the art.

Scheme V shows derivatization of aldehydes of structure 19 using theHorner-Wadsworth-Emmons olefination reaction. Treatment of aldehydes ofstructure 19 with trimethyl phosphonoacetate in the presence of a base,such as, for example, lithium hydroxide, provides α,β-unsaturated estersof structure 28. Hydrolysis of structure 28 is then followed by reationwith an amine in the presence of a coupling agent, such as, for example,benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl-carbodiimide (DCC), to provide amides of structure 29.

Scheme VI shows the synthesis of allylic amines through allylictransposition of allylic acetates of structure 21 with aminenucleophiles. In some embodiments, allylic acetates of structure 21 aretreated with a nucleophile, such as, for example, an amine, in thepresence of a metal catalyst, such as for example, a palladium catalyst,to provide allylic amines of structure 30. Suitable palladium catalystsinclude, but are not limited to, tris(dibenzylacetone)dipalladium(Pd₂(dba)₃), palladium dichloride, bis(acetonitrile)dichloropalladium,and tetrakistriphenylphosphine palladium. Suitable ligands for thepalladium catalyst include, but are not limited to triphenylphosphine.

In other embodiments, allylic acetates of structure 21 are treated withazide, such as, for example, sodium azide, in the presence of a metalcatalyst, such as for example, a palladium catalyst, followed by aStaudinger reaction to provide allylamines of structure 31. Allylaminesof structure 31 can be coupled with a variety of carboxylic acids toprovide amides. Sulfonamides and urea compounds can also be preparedusing allylamines of structure 31.

In some embodiments, the alkene portion of the allylic moiety may behydrogenated to provide the analogous alkyl compounds.

As shown in Scheme VII, amides of structure 33 can be prepared byreacting intermediates of structure 32 with an amines of structure 34.The reaction can be carried out in inert organic solvents such asmethylene chloride, acetonitrile, N,N-dimethylformamide, etherealsolvents such as tetrahydrofuran, dioxane, and the like. The reaction istypically carried out in the presence of a suitable coupling agent,e.g., benzotriazole-1-yloxytrispyrrolidino-phosphoniumhexafluorophosphate (PyBOP®),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl-carbodiimide (DCC), and in the presence of a base(typically 3 equivalents) such as N,N-diisopropylethylamine,triethylamine, N-methylmorpholine, and the like, and optionally in thepresence of 1-hydroxy-benzotriazole (HOBT).

As shown in Scheme VIII, diamines of structure 15 can be reated withbromine in a suitable solvent, such as, for example, chloroform atambient temperature to provide bromo diamines of structure 35. Asdescribed above, diamines of structure 35 is then converted to thebenzimidazoles of structure 36. Cross-coupling chemistry can be used tointroduce a variety of groups in the place of bromine 1n one embodiment,Stille reaction conditions are used, which involves the reaction ofbromo benzimidazoles of structure 36 with an alkyl tributyltin compound,in the presence of a palladium catalyst, such as (PPh3)2PdC12. Solventssuch as 1-methyl-2-pyrrolidinone (NMP) are typically used in the Stillereaction. Alternatively, Sonagashira reaction conditions can be used,which involves the reaction of bromo bromo benzimidazoles of structure36 with a terminal alkyne in the presence of a palladium catalyst, suchas (PPh3)2PdC12, and CuI, and a suitable base, such as triethylamine ina solvent such as THF. Other cross coupling reactions involving arylhalides are known in the art, and involve, but are not limited to, Heckreactions, Suzuki reactions, Negishi reactions, Buchwald-Hartwig crosscoupling reaction, Kumada reactions, and Hiyama cross-couplingreactions.

Alternatively, bromo benzimidazole of structure 36 is treated with acidto form the isoquinolone core. Treatment of structure 38 with an amineunder an atmosphere of carbon monoxide (CO) in the presence of apalladium catalyst, such as, for example, Pd(PPh₃)₄, PdCl₂(Ph₃P)₂, orPd(OAc)₂ in the presence of triphenylphosphine, and a base, such as,tributylamine or N,N-diisopropylethylamine, and optionally a suitableco-solvent such N,N-dimethylacetamide (DMA), N,N-dimethylformamide(DMF), tetrahydrofuran (THF), or dioxane, provides compounds ofstructure 39.

Scheme IX shows a strategy for the synthesis of amides of structure 40.Amides of structure 40 can be prepared by reacting carboxylic acid ofstructure 9 with amine of structure 31. The reaction is performed in thepresence of a coupling agent, such as, for example,benzotriazole-1-yloxytrispyrrolidino-phosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl-carbodiimide (DCC), and in the presence of a base(typically 3 equivalents) such as N,N-diisopropylethylamine,triethylamine, N-methylmorpholine, and the like, and optionally in thepresence of 1-hydroxy-benzotriazole (HOBT). Alternatively, carboxylicacid of structure 9 is first converted to an acid chloride by treatmentwith thionyl chloride or oxalyl chloride and then coupled with amine ofstructure 31.

Using the synthetic methods described herein, as well as those known inthe art, tyrosine kinase inhibitors as disclosed herein are obtained ingood yields and purity. The compounds prepared by the methods disclosedherein are purified by conventional means known in the art, such as, forexample, filtration, recrystallization, chromatography, distillation,and combinations thereof.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Pharmaceutical Composition/Formulation

Compounds disclosed herein have a structure selected from among Formula(Ia), Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula(IIIa), Formula (Mb), Formula (IIIc), Formula (IV), Formula (V), andFormula (VI). It is understood that when reference is made to compoundsdescribed herein, it is meant to include compounds of Formula (Ia),Formula (Ib), Formula (Ic), Formula (II), Formula (III), Formula (IIIa),Formula (Mb), Formula (IIIc), Formula (IV), Formula (V), and Formula(VI), unless otherwise indicated.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

Provided herein are pharmaceutical compositions that include a compounddescribed herein and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In addition, the compounds described hereincan be administered as pharmaceutical compositions in which compoundsdescribed herein are mixed with other active ingredients, as incombination therapy. In some embodiments, the pharmaceuticalcompositions may include other medicinal or pharmaceutical agents,carriers, adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In addition, the pharmaceutical compositionscan also contain other therapeutically valuable substances.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as, but notlimited to, acetic, boric, citric, lactic, phosphoric and hydrochloricacids; bases such as, but not limited to, sodium hydroxide, sodiumphosphate, sodium borate, sodium citrate, sodium acetate, sodium lactateand tris-hydroxymethylaminomethane; and buffers such as, but not limitedto, citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

In other embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds described herein are administered in apharmaceutical composition to a mammal having a disease, disorder, orcondition to be treated. Preferably, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures.

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compounddescribed herein as an active ingredient in free-acid or free-base form,or in a pharmaceutically acceptable salt form. In addition, the methodsand pharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

Certain Pharmaceutical Terminology

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

As used herein, the term “selective inhibitor compound” refers to acompound that selectively inhibits a specific function/activity of oneor more target proteins.

As used herein, the term “selectively inhibits” refers to the ability ofa selective inhibitor compound to inhibit a specific function/activityof a target protein (e.g., the phosphotransferase activity of a kinase)with greater potency than the activity of a non-target protein. Incertain embodiments, selectively inhibiting refers to inhibiting atarget protein activity with a selective inhibitor that has a IC50 thatis at least 10, 50, 100, 250, 500, 1000 or more times lower than forthat of a non-target protein activity.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity.

As used herein, the IC50 refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of tyrosine kinase activity, such as, forexample Btk activity, in an assay that measures such response.

As used herein, EC50 refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of the compound administered, age, weight,general condition of the subject, the condition being treated, theseverity of the condition being treated, and the judgment of theprescribing physician.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound described herein, which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety. In certainembodiments, upon in vivo administration, a prodrug is chemicallyconverted to the biologically, pharmaceutically or therapeutically moreactive form of the compound. In certain embodiments, a prodrug isenzymatically metabolized by one or more steps or processes to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, a pharmaceutically active compound ismodified such that the active compound will be regenerated upon in vivoadministration. The prodrug can be designed to alter the metabolicstability or the transport characteristics of a drug, to mask sideeffects or toxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound. (see, for example, Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392; Silverman (1992), The Organic Chemistry of Drug Designand Drug Action, Academic Press, Inc., San Diego, pages 352-401).

By “pharmaceutically acceptable,” as used herein, refers to a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutically acceptable salts may beobtained by reacting a compound described herein, with acids such as:hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also may be obtained by reacting acompound described herein with a base to form a salt such as an ammoniumsalt, an alkali metal salt, such as a sodium or a potassium salt, analkaline earth metal salt, such as a calcium or a magnesium salt, a saltof organic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like, or by other methods known in the art.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein dosed that is delivered into the general circulation ofthe animal or human being studied. The total exposure (AUC(0-∞)) of adrug when administered intravenously is usually defined as 100%bioavailable (F %). “Oral bioavailability” refers to the extent to whichcompounds disclosed herein are absorbed into the general circulationwhen the pharmaceutical composition is taken orally as compared tointravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsprovided herein in the plasma component of blood of a subject. It isunderstood that the plasma concentration of compounds provided hereinmay vary significantly between subjects, due to variability with respectto metabolism and/or possible interactions with other therapeuticagents. In accordance with one embodiment disclosed herein, the bloodplasma concentration of the compounds provided herein may vary fromsubject to subject. Likewise, values such as maximum plasmaconcentration (C_(max)) or time to reach maximum plasma concentration(T_(max)), or total area under the plasma concentration time curve(AUC(0-∞)) may vary from subject to subject. Due to this variability,the amount necessary to constitute “a therapeutically effective amount”of a compound provided herein may vary from subject to subject.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withcompounds disclosed herein and the release profile properties of thedesired dosage form. Exemplary carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” may include, butare not limited to, acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, polyvinylpyrollidone (PVP), cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

Combinations of one or more erosion facilitator with one or morediffusion facilitator can also be used in the present compositions.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

Dosage Forms

The compositions described herein can be formulated for administrationto a subject via any conventional means including, but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular),buccal, intranasal, rectal or transdermal administration routes. As usedherein, the term “subject” is used to mean an animal, preferably amammal, including a human or non-human The terms patient and subject maybe used interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude a compound provided herein, can be formulated into any suitabledosage form, including but not limited to, aqueous oral dispersions,liquids, gels, syrups, elixirs, slurries, suspensions and the like, fororal ingestion by a patient to be treated, solid oral dosage forms,aerosols, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations for oral administration include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the present invention may be administeredas a single capsule or in multiple capsule dosage form. In someembodiments, the pharmaceutical formulation is administered in two, orthree, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compoundprovided herein, with one or more pharmaceutical excipients to form abulk blend composition. When referring to these bulk blend compositionsas homogeneous, it is meant that the particles of the compound providedherein, are dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms, such as tablets, pills, and capsules. The individual unit dosagesmay also include film coatings, which disintegrate upon oral ingestionor upon contact with diluent. These formulations can be manufactured byconventional pharmacological techniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

The pharmaceutical solid dosage forms described herein can include acompound provided herein and one or more pharmaceutically acceptableadditives such as a compatible carrier, binder, filling agent,suspending agent, flavoring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof. In still other aspects, usingstandard coating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000), a film coating is providedaround the formulation of the compound provided herein. In oneembodiment, some or all of the particles of the compound provided hereinare coated. In another embodiment, some or all of the particles of thecompound provided herein are microencapsulated. In still anotherembodiment, the particles of the compound provided herein are notmicroencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound disclosed herein from a solid dosageform matrix as efficiently as possible, disintegrants are often used inthe formulation, especially when the dosage forms are compressed withbinder. Disintegrants help rupturing the dosage form matrix by swellingor capillary action when moisture is absorbed into the dosage form.Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Formulators skilled in art can determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

The term “non water-soluble diluent” represents compounds typically usedin the formulation of pharmaceuticals, such as calcium phosphate,calcium sulfate, starches, modified starches and microcrystallinecellulose, and microcellulose (e.g., having a density of about 0.45g/cm³, e.g. Avicel, powdered cellulose), and talc.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms of the present invention. The amounts of such additives can bereadily determined by one skilled in the art, according to theparticular properties desired.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compound disclosed herein from the formulation. In otherembodiments, the film coating aids in patient compliance (e.g., Opadry®coatings or sugar coating). Film coatings including Opadry® typicallyrange from about 1% to about 3% of the tablet weight. In otherembodiments, the compressed tablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compound disclosed hereinand one or more excipients are dry blended and compressed into a mass,such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds disclosed herein, which sufficientlyisolate the compound disclosed herein from other non-compatibleexcipients. Materials compatible with compounds disclosed herein arethose that delay the release of the compounds disclosed herein in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds disclosed herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® 5100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® 512.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds disclosed herein may be formulated bymethods known by one of ordinary skill in the art. Such known methodsinclude, e.g., spray drying processes, spinning disk-solvent processes,hot melt processes, spray chilling methods, fluidized bed, electrostaticdeposition, centrifugal extrusion, rotational suspension separation,polymerization at liquid-gas or solid-gas interface, pressure extrusion,or spraying solvent extraction bath. In addition to these, severalchemical techniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used. Furthermore, other methods such asroller compaction, extrusion/spheronization, coacervation, ornanoparticle coating may also be used.

In one embodiment, the particles of compounds disclosed herein aremicroencapsulated prior to being formulated into one of the above forms.In still another embodiment, some or most of the particles are coatedprior to being further formulated by using standard coating procedures,such as those described in Remington's Pharmaceutical Sciences, 20thEdition (2000).

In other embodiments, the solid dosage formulations of the compoundsdisclosed herein are plasticized (coated) with one or more layers.Illustratively, a plasticizer is generally a high boiling point solid orliquid. Suitable plasticizers can be added from about 0.01% to about 50%by weight (w/w) of the coating composition. Plasticizers include, butare not limited to, diethyl phthalate, citrate esters, polyethyleneglycol, glycerol, acetylated glycerides, triacetin, polypropyleneglycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearicacid, stearol, stearate, and castor oil.

In other embodiments, a powder including the formulations with acompound disclosed herein may be formulated to include one or morepharmaceutical excipients and flavors. Such a powder may be prepared,for example, by mixing the formulation and optional pharmaceuticalexcipients to form a bulk blend composition. Additional embodiments alsoinclude a suspending agent and/or a wetting agent. This bulk blend isuniformly subdivided into unit dosage packaging or multi-dosagepackaging units.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the present invention are addedto water, the acids and the base react to liberate carbon dioxide gas,thereby causing “effervescence.” Examples of effervescent salts include,e.g., the following ingredients: sodium bicarbonate or a mixture ofsodium bicarbonate and sodium carbonate, citric acid and/or tartaricacid. Any acid-base combination that results in the liberation of carbondioxide can be used in place of the combination of sodium bicarbonateand citric and tartaric acids, as long as the ingredients were suitablefor pharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound disclosed herein, are solid dispersions. Methods of producingsuch solid dispersions are known in the art and include, but are notlimited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923,5,700,485, 5,723,269, and U.S. Pub. Appl 2004/0013734, each of which isspecifically incorporated by reference. In still other embodiments, theformulations described herein are solid solutions. Solid solutionsincorporate a substance together with the active agent and otherexcipients such that heating the mixture results in dissolution of thedrug and the resulting composition is then cooled to provide a solidblend which can be further formulated or directly added to a capsule orcompressed into a tablet. Methods of producing such solid solutions areknown in the art and include, but are not limited to, for example, U.S.Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each of which isspecifically incorporated by reference.

The pharmaceutical solid oral dosage forms, which include a compounddisclosed herein, can be further formulated to provide a controlledrelease of the compound disclosed herein. Controlled release refers tothe release of the compound disclosed herein from a dosage form in whichit is incorporated according to a desired profile over an extendedperiod of time. Controlled release profiles include, for example,sustained release, prolonged release, pulsatile release, and delayedrelease profiles. In contrast to immediate release compositions,controlled release compositions allow delivery of an agent to a subjectover an extended period of time according to a predetermined profile.Such release rates can provide therapeutically effective levels of agentfor an extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the practice of the present invention toachieve delivery to the lower gastrointestinal tract. In someembodiments the polymers for use in the present invention are anioniccarboxylic polymers. In other embodiments, the polymers and compatiblemixtures thereof, and some of their properties, include, but are notlimited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media ofpH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-555, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound disclosed herein, are delivered using a pulsatile dosage form.A pulsatile dosage form is capable of providing one or more immediaterelease pulses at predetermined time points after a controlled lag timeor at specific sites. Pulsatile dosage forms including the formulationsdescribed herein, which include a compound disclosed herein, may beadministered using a variety of pulsatile formulations known in the art.For example, such formulations include, but are not limited to, thosedescribed in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and5,840,329, each of which is specifically incorporated by reference.Other pulsatile release dosage forms suitable for use with the presentformulations include, but are not limited to, for example, U.S. Pat.Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and5,837,284, all of which are specifically incorporated by reference. Inone embodiment, the controlled release dosage form is pulsatile releasesolid oral dosage form including at least two groups of particles, (i.e.multiparticulate) each containing the formulation described herein. Thefirst group of particles provides a substantially immediate dose of thecompound disclosed herein upon ingestion by a mammal. The first group ofparticles can be either uncoated or include a coating and/or sealant.The second group of particles includes coated particles, which includesfrom about 2% to about 75%, preferably from about 2.5% to about 70%, andmore preferably from about 40% to about 70%, by weight of the total doseof the compound disclosed herein in said formulation, in admixture withone or more binders. The coating includes a pharmaceutically acceptableingredient in an amount sufficient to provide a delay of from about 2hours to about 7 hours following ingestion before release of the seconddose. Suitable coatings include one or more differentially degradablecoatings such as, by way of example only, pH sensitive coatings (entericcoatings) such as acrylic resins (e.g., Eudragit® EPO, Eudragit®L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit®5100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5, Eudragit® 512.5,and Eudragit® NE30D, Eudragit® NE 40D®) either alone or blended withcellulose derivatives, e.g., ethylcellulose, or non-enteric coatingshaving variable thickness to provide differential release of theformulation that includes a compound disclosed herein.

Many other types of controlled release systems known to those ofordinary skill in the art and are suitable for use with the formulationsdescribed herein. Examples of such delivery systems include, e.g.,polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2ndEd., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983, each of which is specificallyincorporated by reference.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds disclosed herein and at least onedispersing agent or suspending agent for oral administration to asubject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to the particles of compound disclosed herein, the liquiddosage forms may include additives, such as: (a) disintegrating agents;(b) dispersing agents; (c) wetting agents; (d) at least onepreservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, for example, hydrophilic polymers, electrolytes, Tween® 60 or80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMCK100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®,e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethyleneoxide and formaldehyde (also known as tyloxapol), poloxamers (e.g.,Pluronics F68®, F88®, and F108®, which are block copolymers of ethyleneoxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, alsoknown as Poloxamine 908®, which is a tetrafunctional block copolymerderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein are known in the art and include, but are not limitedto, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethyleneglycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (UnionCarbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodiumlauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodiumtaurocholate, simethicone, phosphotidylcholine and the like

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Inone embodiment, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.001% toabout 1.0% the volume of the aqueous dispersion. In another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.005% to about0.5% the volume of the aqueous dispersion. In yet another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.01% to about1.0% the volume of the aqueous dispersion.

In addition to the additives listed above, the liquid formulations canalso include inert diluents commonly used in the art, such as water orother solvents, solubilizing agents, and emulsifiers. Exemplaryemulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodiumdoccusate, cholesterol, cholesterol esters, taurocholic acid,phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563, each of which is specifically incorporated by reference.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein. The amounts ofsuch additives can be readily determined by one skilled in the art,according to the particular properties desired.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations thatinclude a compound provided herein, which are prepared according tothese and other techniques well-known in the art are prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents known in the art. See, for example, Ansel, H. C. et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995).Preferably these compositions and formulations are prepared withsuitable nontoxic pharmaceutically acceptable ingredients. Theseingredients are known to those skilled in the preparation of nasaldosage forms and some of these can be found in REMINGTON: THE SCIENCEAND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference inthe field. The choice of suitable carriers is highly dependent upon theexact nature of the nasal dosage form desired, e.g., solutions,suspensions, ointments, or gels. Nasal dosage forms generally containlarge amounts of water in addition to the active ingredient. Minoramounts of other ingredients such as pH adjusters, emulsifiers ordispersing agents, preservatives, surfactants, gelling agents, orbuffering and other stabilizing and solubilizing agents may also bepresent. Preferably, the nasal dosage form should be isotonic with nasalsecretions.

For administration by inhalation, the compounds disclosed herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal Formulations

Buccal formulations that include compounds disclosed herein may beadministered using a variety of formulations known in the art. Forexample, such formulations include, but are not limited to, U.S. Pat.Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which isspecifically incorporated by reference. In addition, the buccal dosageforms described herein can further include a bioerodible (hydrolysable)polymeric carrier that also serves to adhere the dosage form to thebuccal mucosa. The buccal dosage form is fabricated so as to erodegradually over a predetermined time period, wherein the delivery of thecompound disclosed herein is provided essentially throughout. Buccaldrug delivery, as will be appreciated by those skilled in the art,avoids the disadvantages encountered with oral drug administration,e.g., slow absorption, degradation of the active agent by fluids presentin the gastrointestinal tract and/or first-pass inactivation in theliver. With regard to the bioerodible (hydrolysable) polymeric carrier,it will be appreciated that virtually any such carrier can be used, solong as the desired drug release profile is not compromised, and thecarrier is compatible with the compound disclosed herein, and any othercomponents that may be present in the buccal dosage unit. Generally, thepolymeric carrier comprises hydrophilic (water-soluble andwater-swellable) polymers that adhere to the wet surface of the buccalmucosa. Examples of polymeric carriers useful herein include acrylicacid polymers and co, e.g., those known as “carbomers” (Carbopol®, whichmay be obtained from B.F. Goodrich, is one such polymer). Othercomponents may also be incorporated into the buccal dosage formsdescribed herein include, but are not limited to, disintegrants,diluents, binders, lubricants, flavoring, colorants, preservatives, andthe like. For buccal or sublingual administration, the compositions maytake the form of tablets, lozenges, or gels formulated in a conventionalmanner

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144, each of which is specifically incorporated by reference inits entirety.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compounddisclosed herein; (2) a penetration enhancer; and (3) an aqueousadjuvant. In addition, transdermal formulations can include additionalcomponents such as, but not limited to, gelling agents, creams andointment bases, and the like. In some embodiments, the transdermalformulation can further include a woven or non-woven backing material toenhance absorption and prevent the removal of the transdermalformulation from the skin. In other embodiments, the transdermalformulations described herein can maintain a saturated or supersaturatedstate to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds disclosed herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Injectable Formulations

Formulations that include a compound disclosed herein, suitable forintramuscular, subcutaneous, or intravenous injection may includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Other Formulations

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the inhibition of tyrosine kinase activity, such as Btkactivity, or for the treatment of diseases or conditions that wouldbenefit, at least in part, from inhibition of Btk activity. In addition,a method for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofpharmaceutical compositions containing at least one compound disclosedherein, or a pharmaceutically acceptable salt, pharmaceuticallyacceptable N-oxide, pharmaceutically active metabolite, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dosemay conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.01 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, including, but not limitedto, humans, is in the range from about 0.5 mg to about 300 mg,conveniently administered in divided doses, including, but not limitedto, up to four times a day or in extended release form. Suitable unitdosage forms for oral administration include from about 1 to 200 mgactive ingredient. The foregoing ranges are merely suggestive, as thenumber of variables in regard to an individual treatment regime islarge, and considerable excursions from these recommended values are notuncommon. Such dosages may be altered depending on a number ofvariables, not limited to the activity of the compound used, the diseaseor condition to be treated, the mode of administration, the requirementsof the individual subject, the severity of the disease or conditionbeing treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD50 (the dose lethal to 50% of the population) and the ED50 (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD50 and ED50. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human The dosage of such compounds liespreferably within a range of circulating concentrations that include theED50 with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The tyrosine inhibitor compositions described herein can also be used incombination with other well known therapeutic reagents that are selectedfor their therapeutic value for the condition to be treated. In general,the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of the skilledclinician. The initial administration can be made according toestablished protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

In certain instances, it may be appropriate to administer at least onetyrosine kinase inhibitor compound described herein in combination withanother therapeutic agent. By way of example only, if one of the sideeffects experienced by a patient upon receiving one of the tyrosinekinase inhibitor compounds described herein is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literatureCombination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula Ia, Ib, IIa, or IIb described herein) may be administered inany order or even simultaneously. If simultaneously, the multipletherapeutic agents may be provided in a single, unified form, or inmultiple forms (by way of example only, either as a single pill or astwo separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound dislcosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over 5 minutes toabout 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. The length of treatment can vary for eachsubject, and the length can be determined using the known criteria. Forexample, the compound or a formulation containing the compound can beadministered for at least 2 weeks, preferably about 1 month to about 5years, and more preferably from about 1 month to about 3 years.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease, disorder, or condition that wouldbenefit by inhibition of Bruton's tyrosine kinase activity or in whichBruton's tyrosine kinase activity is a mediator or contributor to thesymptoms or cause.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally include an identifyingdescription or label or instructions relating to its use in the methodsdescribed herein.

A kit may include one or more additional containers, each with one ormore of various materials (such as reagents, optionally in concentratedform, and/or devices) desirable from a commercial and user standpointfor use of a compound described herein. Non-limiting examples of suchmaterials include, but not limited to, buffers, diluents, filters,needles, syringes; carrier, package, container, vial and/or tube labelslisting contents and/or instructions for use, and package inserts withinstructions for use. A set of instructions will also typically beincluded.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

Exemplary Therapeutic Agents for Use in Combination with a TyrosineKinase Inhibitor Compound

Agents for Treating Autoimmune Diseases, Inflammatory Diseases, orAllergy Diseases

Where the subject is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease, antyrosine kinase inhibitor compound can be used in with one or more ofthe following therapeutic agents in any combination: immunosuppressants(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720), glucocorticoids (e.g., prednisone, cortisone acetate,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Anti-Cancer Agents

Where the subject is suffering from or at risk of suffering from aB-cell proliferative disorder (e.g., plasma cell myeloma), the subjectedcan be treated with a tyrosine kinase inhibitor compound in anycombination with one or more other anti-cancer agents. In preferredembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is an anti-cancer drugwhich acts by enhancing and stabilizing microtubule formation, andanalogs of Taxol™, such as Taxotere™. Compounds that have the basictaxane skeleton as a common structure feature, have also been shown tohave the ability to arrest cells in the G2-M phases due to stabilizedmicrotubules and may be useful for treating cancer in combination withthe compounds of the invention.

Further examples of anti-cancer agents for use in combination with atyrosine kinase inhibitor compound include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002.

Other anti-cancer agents that can be employed in combination with atyrosine kinase inhibitor compound include Adriamycin, Dactinomycin,Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin Il (including recombinant interleukin II, or r1L2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with atyrosine kinase inhibitor compound include: 20-epi-1, 25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MT inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other anticancer agents that can be employed in combination with atyrosine kinase inhibitor compound include alkylating agents,antimetabolites, natural products, or hormones, e.g., nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,ete.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a tyrosinekinase inhibitor compound include but are not limited to vinca alkaloids(e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that can be employed in combination atyrosine kinase inhibitor compound include, but are not limited to,nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, ete.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with atyrosine kinase inhibitor compound include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions of the invention forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with a tyrosine kinase inhibitor compound include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCl), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Agents for Treating Thromboembolic Disorders

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated witha tyrosine kinase inhibitor compound in any combination with one or moreother anti-thromboembolic agents. Examples of anti-thromboembolic agentsinclude, but are not limited any of the following: thrombolytic agents(e.g., alteplase anistreplase, streptokinase, urokinase, or tissueplasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g.,dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux,draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150),ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, orBIBR 1048.

In some embodiments, compounds provided herein may be administered incombination with one or more compound(s) selected from azathioprine,plaquenil, prednisone, sulfasalazine, methotrexate, Arava, Remicade, andEnbrel.

In other embodiments, compounds provided herein may be administered incombination with one or more compound(s) selected from an estrogenreceptor modulator, an androgen receptor modulator, retinoid receptormodulator, a cytotoxic agent, another antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, and anangiogenesis inhibitor.

In yet other embodiments, compounds provided herein may be administeredin combination with one or more chemotherapeutic compound(s) selectedfrom among Taxol®, Taxotere®, epothilone A, epothilone B,desoxyepothilone A, desoxyepothilone B or their derivatives;epidophyllotoxin; procarbazine; mitoxantrone; the mitomycins,discodermolide, podophyllotoxins, doxorubicin, caminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, Herceptin®, Rituxan®,5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside,colchicines, etoposide, etoposide phosphate, teniposide, melphalan,vinblastine, vincristine, vinorelbein, leurosidine, vindesine,leurosine, paclitaxel, estramustine, cisplatin, carboplatin,cyclophosphamide, bleomycin, tamoxifen, ifosamide, melphalan, hexamethylmelamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine,L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide,flutamide, leuprolide, pyridobenzoindole derivatives, interferons,interleukins, capecitabine, and gefitinib.

In yet other embodiments, compounds provided herein may be administeredin combination with a β-2 adrenoreceptor agonist, corticosteroid,leukotriene antagonist, phosphodiesterase 4 inhibitor, and/orantihistamine. In further embodiments, compounds provided herein may beadministered in combination with one or more compound(s) selected fromsalmeterol, fluticasone, budesonide, montelukast, levalbuterol, androflumilast.

EXAMPLES

The person skilled in the art may further appreciate various aspects andadvantages of the present disclosure upon review of the followingillustrative and non-limiting examples:

Synthesis of Compounds Intermediate 1: 4-Methyl-[1,4]azaphosphinane4-oxide hydrochloride

Step 1

A solution of methylphosphonic dichloride (9.92 g, 74.6 mmol) in THF (75mL) at −78° C. was treated with vinylmagnesium bromide in THF (175 mL,1.0M), which was added over 4 hours via an addition funnel. The solutionwas warmed to 0° C. and quenched with saturated. NH₄Cl. The solventswere evaporated under reduced pressure and the residue was trituratedwith 1:1 THF/ethyl acetate several times to extract the divinyl methylphosphine oxide product, which was used directly without furtherpurification.

Step 2

A solution of methyl divinyl phosphine oxide (10.73 g, 92.4 mmol) andbenzylamine (11.6 mL, 106.3 mmol) in 1:1 THF/water (250 mL) was heatedat reflux for 16 hours. The solvents were removed under reducedpressure. The residue was crystallized from CH₂Cl₂/ether to give1-benzyl-4-methyl-[1,4]azaphosphinane 4-oxide as a white solid (13.24 g,64%). ¹H NMR (400 MHz, DMSO) δ 7.13-3.37 (5H, m); 3.6 (2H, s); 2.81 (2H,m); 2.59 (2H, m); 1.7-1.9 (4H, m); 1.42 (3H, d, JH—C—P=13.6 Hz). ³¹P NMRδ 32 ppm.

Step 3

1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol(100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon(10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hoursat 50 psi. The mixture was filtered through Celite and all solvents wereremoved under reduced pressure. The product was triturated in hotethanol (50 mL) and cooled, and the solution was diluted with ether (300mL). The white crystalline solid was filtered, washed with ether (2×50mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g,94%). ¹H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H);1.61 (m, 2H), 1.39 (3H, d, JH—C—P=13.6 Hz.); ³¹P NMR: δ 29 ppm; ESMS(m/z): (M+1)⁺. found, 134.

Intermediate 2: 4-Methyl-[1,4]azaphosphinane 4-oxide

Step 1

To a scintillation vial was added 4-methyl-[1,4]azaphosphinane 4-oxidehydrochloride (0.2 g, 1.18 mmol), carbonate resin (1.0 g, MP-carbonate,Argonaut, 2.5-3 mmol/g, obtained from Argonaut Technologies, Inc., 220Saginaw Drive, Redwood City, Calif. 94063, USA), methanol (2 mL), andTHF (2 mL). The mixture was stirred at room temperature for 1 hour, thenfiltered and concentrated in vacuo.

Intermediate 3: 4-Phenyl-[1,4]azaphosphinane 4-oxide hydrochloride

Step 1

A solution of phenylphosphonic dichloride (29 mL, 200 mmol) dissolved inanhydrous THF (600 mL) was cooled to −78° C. and mechanically stirredunder an atmosphere of dry nitrogen. Vinylmagnesium bromide (1M in THF,500 mL) was slowly added so that the temperature of the reaction mixturenever exceeded −70° C. The addition took 2 hours. After an additional 1hour of stirring at −78° C., the cold reaction mixture was poureddirectly into cold, saturated NH₄Cl(1 L). The mixture was extractedtwice with CH₂Cl₂ and the combined organic phase was washed with 1 MNaOH, brine, and then dried over Mg₂SO₄. Filtration and solventevaporation provided divinyl-phenyl-phosphine oxide (26.8 g, 75%) as aviscous yellow oil that solidified upon standing. ¹H NMR (400 MHz,DMSO-d6); δ 7.8-7.4 (m, 5H), 6.7 (m, 2H), 6.4-6.1 (m, 4H). ³¹P NMR(DMSO-d6); δ 17.0 (s).

Step 2

Divinyl-phenyl-phosphine oxide (26.5 g, 149 mmol) and benzylamine (17.9mL, 164 mmol) were dissolved in 50% aq. THF (400 mL) and heated toreflux under nitrogen for 38 hours. The cooled reaction mixture waspartitioned between saturated aqueous NaHCO₃ and CH₂Cl₂. The aqueousphase was washed once more with CH₂Cl₂ and the combined organic phasewas washed with brine and dried over MgSO₄. Filtration and solventevaporation gave 29 g of a yellow oil, which was purified by flashchromatography on silica gel, eluting with 0-10% MeOH in EtOAc.1-Benzyl-4-phenyl-[1,4]azaphosphinane 4-oxide was obtained as a yellowsolid (25.5 g, 60%). ¹H NMR (400 MHz, DMSO-d6); δ 7.8 (m, 2H), 7.55 (m,3H), 7.3 (m, 5H), 3.65 (s, 2H), 2.8 (m, 4H), 2.25 (m, 2H), 1.9 (broad t,2H). ³¹P NMR (DMSO-d6); δ 27.0 (s).

Step 3

1-Benzyl-4-phenyl-[1,4]azaphosphinane 4-oxide (14.2 g, 49.8 mmol) wasdissolved in absolute EtOH (65 mL) and 1N HCl (50 mL). Palladium oncarbon (10%, 2.0 g) was added and the mixture was hydrogenated on a Parrshaker at 50 psi for 60 hours. After filtration through Celite, thefiltrate was rotovapped and the residue was triturated with ether togive 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride, as an off-whitesolid (11.40 g, 99%). ¹H NMR (400 MHz, DMSO-d6) δ 7.85 (m, 2H), 7.65 (m,3H), 3.5 (m, 4H), 2.7 (m, 2H), 2.2 (broad t, 2H). ³¹P NMR (DMSO-d6); δ24.0 (s).

The free base of 4-phenyl-[1,4]azaphosphinane 4-oxide hydrochloride wasobtained using procedures similar to those described in Intermediate 2and Example 3, Step 6.

Intermediate 4: 4-(4-Fluorophenylmethyl)-[1,4]azaphosphinane 4-oxidehydrochloride

Step 1

4-fluorobenzyl bromide (25 mL, 0.20 mol) was added to a stirred solutionof trimethyl phosphite (35.9 mL, 0.30 mol) at ambient temperature, undera nitrogen atmosphere. The resulting solution was heated at 110° C. forsix hours, and then at 90° C. overnight. The reaction mixture wasallowed to cool to ambient temperature and then ethyl acetate (350 mL)was added. The solution was washed with saturated sodium bicarbonate(350 mL) and then with saturated brine (2×350 mL). The organic phase wasdried with magnesium sulfate, filtered, and concentrated by rotatryevaporation. The resulting crude product was purified by flash silicachromatrography using 0-35% acetonitrile in ethyl acetate as eluant toyield (4-fluoro-benzyl)-phosphonic acid dimethyl ester (29.44 g, 135mmol, 66% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 7.33-7.28(m, 2H); 7.17-7.12 (dd, 2H); 3.61-3.58 (d, 6H); 3.31-3.24 (d, 2H); ESMS(m/z): (M+1)⁺. found, 219.

Step 2

Bromotrimethylsilane (6.0 mL, 45.4 mmol) was added dropwise to(4-fluoro-benzyl)-phosphonic acid dimethyl ester (4.57 g, 20.95 mmol)and stirred in a reaction flask chilled to 0° C. The resulting solutionwas allowed to warm to ambient temperature and stirred for an additionalhour, then concentrated by rotary evaporation to remove volatilesyielding crude (4-fluoro-benzyl) phosphonic acidbis(trimethylsilyl)ester which was used without further purification.

Step 3

To (4-fluoro-benzyl)phosphonic acid bis(trimethylsilyl)ester was added25 mL of dry methylene chloride, 12 drops of dry DMF, followed bydropwise addition of 6 mL of oxalyl chloride (68.3 mmol). The resultingsolution was stirred overnight at ambient temperature as gas wasgenerated. The reaction was concentrated by rotary evaporation to yield5.2 g of a yellow waxy solid that was purified by distillation atreduced pressure to yield 1.71 g (37%) of 4-fluorobenzyl phosphonicdichloride as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m,2H); 7.11-7.05 (m, 2H); 3.93-3.87 (d, 2H).

Step 4

4-Fluorobenzyl phosphonic dichloride (1.71 g, 7.82 mmol) was dissolvedin 10 mL of dry THF, under a nitrogen atmosphere, and chilled to −70° C.To this stirred solution was added dropwise vinyl magnesium bromide inTHF (18.3 mL, 1M). The resulting solution was stirred for 30 minutes at−70° C. An aqueous solution of ammonium chloride (100 mL, 2M) waschilled to 0° C. and stirred rapidly while the cold reaction mixture wasadded. The product was extracted into dichloromethane and washed withsaturated aqueous sodium bicarbonate, and then with water. The organicphase was dried with sodium sulfate, filtered, and concentrated byrotary evaporation to yield 1.375 g of (4-fluorophenylmethyl)divinylphosphine oxide (6.55 mmol, 84%) as a white solid. ¹H NMR (400 MHz,CDCl₃) 7.20-7.14 (m, 2H); 7.01-6.95 (m 2H); 6.29-6.08 (m, 6H); 3.20-3.15(d, 2H); ESMS (m/z): (M+1)⁺. found, 211.

Step 5

Divinyl-(4-Fluorophenylmethyl)-phosphine oxide (0.719 g, 3.42 mmol) andbenzylamine (0.45 mL, 4.11 mmol) were dissolved in a mixture of THF (15mL) and deionized water (15 mL). The reaction mixture was heated at 82°C. for 22 hours. The reaction was not complete and so an additional 0.04mL of benzylamine was added and the reaction mixture was heated for anadditional six hours at 90° C. The reaction mixture was concentrated byrotary evaporation and the product was extracted into dichloromethaneand washed with saturated brine. The organic phase was dried with sodiumsulfate, filtered, and concentrated by rotary evaporation. The crudeproduct was taken up in 1:1 ethyl acetate:dichloromethane and passedthrough a plug of silica. The product was then eluted from the silicawith a solution of 10% methanol in ethyl acetate. The solvents wereremoved by rotary evaporation to yield 0.84 g of1-benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide (2.65mmol, 77%). ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.25 (m, 5H); 7.25-7.20 (m,2H); 7.04-6.98. (m, 2H); 3.6 (s, 2H); 3.17-3.12 (d, 2H); 3.00-2.85 (m,2H); 2.81-2.66 (m, 2H); 1.98-1.75 (m, 4H).

Step 6

1-Benzyl-4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide wasdissolved in ethanol (100 mL). Aqueous HCl (5.2 mL, 1M) and of water (20mL) were added. The solution was degassed with a stream of nitrogen andthen palladium on carbon (10%, 0.5 g) was added. The mixture washydrogenated on a Parr shaker overnight at 60 psi. The mixture wasfiltered through Celite and all solvents were removed under reducedpressure. The product was recrystallized from methanol/diethyl ether toyield 0.659 g (2.50 mmol, 93%) of4-(4-fluorophenylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride as awhite crystalline solid, ¹H NMR (400 MHz, DMSO) δ 7.38-7.32 (m, 2H);7.23-7.18 (m, 2H) 3.46-3.36 (m, 6H); 2.10-1.96 (m, 4H); ESMS (m/z):(M+1)⁺. found, 228; (M+23)⁺. found, 250.

The free base of 4-(4-fluorophenylmethyl-[1,4]azaphosphinane 4-oxidehydrochloride was obtained using procedures similar to Intermediate 2and Example 3, Step 6.

Intermediate 5: 4-(cyclopropylmethyl)-[1,4]azaphosphinane 4-oxidehydrochloride

Step 1

Bromomethyl-cyclopropane (26.00 g, 0.193 mol) was added to triisopropylphosphite (35.9 mL, 0.30 mol) at ambient temperature, under a nitrogenatmosphere. The resulting solution was stirred and heated at reflux(144° C. bath temperature) overnight. The reaction mixture was allowedto cool to ambient temperature and then ethyl acetate (350 mL) wasadded. The solution was washed with saturated sodium bicarbonate (350mL) and then with saturated brine (2×350 mL). The organic phase wasdried with magnesium sulfate, filtered, and concentrated by rotaryevaporation and then under high vacuum to yield 39.96 g ofcyclopropylmethyl-phosphonic acid diisopropyl ester (0.182 mol, 94%yield) as a colorless oil. ¹H NMR (400 MHz, DMSO) δ 4.63-4.54 (m, 2H);1.67-1.60 (d of d, 2H) 1.27-1.24 (d of d, 12H); 0.85-0.75 (m, 1H);0.52-0.46 (m, 2H); 0.21-0.16 (m, 2H); ESMS (m/z): (M+1)⁺. found, 221;(M+23)⁺. found, 243.

Step 2

Bromotrimethylsilane (43 mL, 0.326 mol) was added dropwise tocyclopropylmethyl-phosphonic acid diisopropyl ester (18.00 g, 81.8 mmol)stirred in a reaction flask chilled to 5° C. The resulting solution wasallowed to warm to ambient temperature, stirred for three hours, andthen concentrated by rotary evaporation yielding crudecyclopropylmethyl-phosphonic acid bis(trimethylsilyl)ester which wasused without further purification.

Step 3

To the cyclopropylmethyl-phosphonic acid bis(trimethylsilyl)ester fromStep 2 was added dry methylene chloride (100 mL), dry DMF (2 mL), thendropwise of oxalyl chloride (23.3 mL, 267 mmol). The resulting solutionwas stirred overnight at ambient temperature. The reaction wasconcentrated by rotary evaporation to yield 16.03 g of a yellow waxysolid that was purified by distillation at reduced pressure to yield8.50 g of cyclopropylmethyl-phosphonic dichloride (49.1 mmol, 60%) aswhite solid. ¹H NMR (400 MHz, DMSO) δ 1.57-1.45 (m, 2H); 0.95-0.75 (m,1H) 0.53-0.43 (m, 2H); 0.24-0.12 (m, 2H).

Step 4

Cyclopropylmethyl-phosphonic dichloride (8.43 g, 48.7 mmol) wasdissolved in dry THF (70 mL), placed under a nitrogen atmosphere, andchilled to −70° C. To this stirred solution was added dropwise vinylmagnesium bromide in THF (122 mL, 1M). The resulting solution wasstirred for 90 minutes at −70° C. An aqueous solution of ammoniumchloride (500 mL, 2M) was chilled to 0° C. and stirred rapidly while thecold reaction mixture was added. The product was extracted intodichloromethane and washed with saturated aqueous sodium bicarbonate andthen with water. The organic phase was dried with sodium sulfate,filtered, and concentrated by rotary evaporation to yield 3.56 g of(cyclopropylmethyl)-divinyl-phosphine oxide (22.8 mmol, 47%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 6.44-6.14 (m, 6H); 1.84-1.78 (d of d,2H) 0.98-0.86 (m, 1H); 0.66-0.60 (m, 2H); 0.25-0.19 (m, 2H); ESMS (m/z):(M+1)⁺. found, 157; (M−1)⁻. found, 155.

Step 5

Cyclopropylmethyl)-divinyl-phosphine oxide (3.56, 22.8 mmol) andbenzylamine (3.0 mL, 27.4 mmol) were dissolved in a mixture of THF (100mL) and deionized water (100 mL). The reaction mixture was heated at 90°C. for 24 hours. The reaction was not complete and so additionalbenzylamine (1.0 mL, 9.1 mmol) was added and the reaction mixture washeated for an additional six hours at 90° C. The reaction mixture wasconcentrated by rotary evaporation and the product was extracted intodichloromethane and washed with saturated brine. The organic phase wasdried with sodium sulfate, filtered, and concentrated by rotaryevaporation. The crude product was taken up in ethyl acetate and passedthrough a plug of silica. The product was then eluted from the silicawith ethanol. The solvents were removed by rotary evaporation to yield4.835 g of 1-benzyl-4-(cyclopropylmethyl)-[1,4]azaphosphinane 4-oxide(18.38 mmol, 81%) as an off-white crystalline solid. ¹H NMR (400 MHz,DMSO) δ 7.38-7.30 (m, 4H); 7.30-7.24 (m, 1H); 3.59 (s, 2H); 2.81-2.63(m, 4H); 1.94-1.83 (m, 2H); 1.82-1.71 (m, 2H); 1.74-1.68 (d of d, 2H);0.96-0.83 (m, 1H); 0.56-0.49 (m, 2H); 0.22-0.14 (m, 2H); ESMS (m/z):(M+1)⁺. found, 264; (M+23)⁺. found, 286.

Step 6

The material from Step 5 was dissolved in ethanol (80 mL) and aqueousHCl (40 mL, 1M) was added. The solution was degassed with a stream ofnitrogen and palladium on carbon (10%, 1.0 g) was added. The mixture washydrogenated on a Parr shaker overnight at 20 psi. The reaction mixturewas filtered through Celite and the solvents were removed under reducedpressure. The product was dissolved in methanol, and benzene was added.The solvents were removed by rotary evaporation. The product wasrecrystallized from ethanol/diethyl ether to yield 3.526 g of4-(cyclopropylmethyl-[1,4]azaphosphinane 4-oxide hydrochloride (16.83mmol, 92%) as a white crystalline solid. ¹H NMR (400 MHz, DMSO)9.60-9.30 (d, 2H); 3.42-3.29 (m, 4H); 2.32-2.21 (m, 2H); 2.16-2.03 (m,2H); 1.91-1.85 (d of d, 2H); 0.95-0.85 (m, 1H); 0.59-0.51 (m, 2H);0.26-0.20 (m, 2H); ESMS (m/z): (M+1)⁺. found, 174; (M+23)⁺. found, 196.

The free base of 4-(cyclopropylmethyl-[1,4]azaphosphinane 4-oxidehydrochloride was obtained using procedures similar to Intermediate 2.

Intermediate 6: 4-Cyclopropyl-[1,4]azaphosphinane 4-oxide HBF₄

Step 1

To a 200 mL round-bottom flask equipped with a magnetic stir-bar wasadded phosphorochloridic acid diethyl ester (17.25 mL, 120 mmole) andTHF (200 mL). The mixture was cooled to −78° C. and a solution ofcyclopropylmagnesium bromide (200 mL, 0.5 M in THF, 100 mmol) was addeddropwise over 30 minutes using an addition funnel. The reaction wasallowed to slowly warm to room temperature overnight. The resultingclear reaction mixture was poured into saturated NH₄Cl (200 mL) andpartitioned. The product was extracted from the aqueous layer withdiethyl ether (1×100 mL). The organic fractions were combined, driedover sodium sulfate, and concentrated in vacuo. The resulting yellow oilwas further purified by vacuum distillation (65-75° C. at 500 mTorr) toprovide cyclopropylphosphonic acid diethyl ester (9.025 g, 51%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.11-4.03 (m, 4H), 1.32-1.29(m, 6H), 0.90-0.77 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ ppm 61.7 (d,J=5.3 Hz), 16.4 (d, J=6.1 Hz), 3.3 (d, J=196.3 Hz), 3.0 (d, J=4.6 Hz).

Step 2

To a 250 mL round bottom flask equipped with a stir-bar was addedcyclopropyl phosphonic acid diethyl ester (9.03 g, 51 mmol). The neatsolution was cooled to 4° C. by immersion in an ice-water bath. To therapidly stirred solution was then added trimethylsilyl bromide (20.1 mL,152 mmol) slowly via syringe. The addition was exothermic and thereaction mixture gently auto-refluxed for several minutes. The ice bathwas allowed to warm to room temperature after the addition and thereaction was stirred for an additional 1.5 hours. All volatile reactioncomponents were then removed in vacuo to give the trimethylsilyl esteras a light yellow oil which was used in the next step without furtherpurification.

Step 3

Methylene chloride (75 mL) and DMF (200 μl) were added to the product ofstep 2 (in the same flask). Oxalyl chloride (12.8 mL, 152 mmol) wasadded dropwise to the stirring reaction mixture, which was vented toair. Vigorous gas evolution was observed upon addition, which continuedfor several hours. The vented reaction mixture was stirred overnight,and then all volatile components were removed in vacuo to produce a darkbrown syrup. The crude reaction mixture was further purified bybulb-to-bulb distillation (115° C., 5.0 Ton) to give cyclopropylphosphonic dichloride (3.7 g, 45%) as a light-yellow free flowing oil.¹H NMR (400 MHz, CDCl₃) δ 1.80-1.65 (m, 1H), 1.40-1.08 (m, 4H); ¹³C NMR(100 MHz, CDCl₃) δ 20.7 (d, J=151.8 Hz), 6.9 (d, J=5.3 Hz).

Step 4

To a 250 mL round-bottom flask equipped with a magnetic stir-bar wasadded cyclopropyl phosphonic dichloride (2.33 g, 14.7 mmol) and THF (100mL). The solution was cooled to −78° C. and vinylmagnesium bromide (58.8mmol, 1.0 M solution in THF) was added dropwise over 15 minutes. Thesolution was stirred at −78° C. for 7 hours and then poured, while stillcold, into saturated aqueous NH₄Cl (200 mL). The resulting solution wasextracted with DCM (3×100 mL). The organic layers were combined, washedwith brine (2×100 mL), dried over sodium sulfate and concentrated invacuo to provide cyclopropyl-divinyl-phosphine oxide (0.811 g, 39%) as alight-brown free-flowing oil which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 6.40-6.00 (m, 6H), 0.98-0.80 (m,5H); GC-CIMS (m/z): (M+1)⁺. found, 142.

Step 5

To a 100 mL round-bottom flask equipped with a magnetic stir-bar wasadded cyclopropyl-divinyl-phosphine oxide (0.81 g, 5.7 mmol), THF (20mL), water (20 mL) and benyzlamine (0.73 g, 6.8 mmol). The flask wasequipped with a reflux condenser and heated to 85° C. for 16 hours. TheTHF was removed in vacuo and the resulting cloudy aqueous solution wasextracted with DCM. The organic layers were collected, washed withbrine, dried over sodium sulfate, and concentrated to provide a yellowoil. The product was further purified by column chromatography elutingwith MeOH/HCCl₃ (0-10%) to provide1-benzyl-4-cyclopropyl-[1,4]azaphosphinane 4-oxide (0.77 g, 54%) as alight-yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 5H), 3.35 (s,2H), 2.82-2.73 (m, 4H), 1.89-1.73 (m, 4H), 1.09-1.01 (m, 1H), 0.83-0.61(m, 4H); ESMS (m/z). found, 250.

Step 6

To a 500 mL Parr pressure flask was added1-benzyl-4-cyclopropyl-[1,4]azaphosphinane 4-oxide (0.77 g, 3.1 mmol),ethanol (50 mL), and 1N aqueous HCl (50 mL). To the solution was thenadded palladium on carbon (10% w/w, 0.4 g), and the flask waspressurized to 30 psi with shaking. After 48 hours, the catalyst wasremoved by filtration and the reaction was concentrated in vacuo toproduce a waxy solid. The crude product was re-dissolved in a methanolicHBF₄ solution (5% v/v) and allowed to crystallize over 24 hours by vapordiffusion of diethyl ether. The resulting crystals were isolated byfiltration to provide 4-cyclopropyl-[1,4]azaphosphinane 4-oxide HBF₄salt (0.12 g, 16%) as white needles. ¹H NMR (400 MHz, d6-DMSO) δ ppm8.61 (s, 2H), 3.46-3.39 (m, 4H), 2.10-1.99 (m, 4H), 1.26-1.18 (m, 1H),0.86-0.70 (m, 4H); ESMS (m/z). found, 160.

The free base of 4-cyclopropyl-[1,4]azaphosphinane 4-oxide HBF₄ salt wasobtained using procedures similar to Intermediate 2.

Intermediate 7: 4-(4-Fluorophenyl)-[1,4]azaphosphinane 4-oxidehydrochloride

Step 1

4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethylphosphite (8.86 mL, 68.8 mmol) at ambient temperature, followed by theaddition of triethylamine (9.6 mL, 68.8 mmol). The resulting solutionwas degassed with nitrogen followed by the addition oftetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol). The resultingmixture was heated at 90° C. overnight. The reaction mixture was allowedto cool to ambient temperature and then ethyl acetate (350 mL) wasadded. The solution was washed with saturated sodium bicarbonate (350mL) and then with saturated brine (2×350 mL). The crude product waspurified by vacuum distillation (ca. 98° C., 0.6 Ton) to yield 8.956 gof 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.80 (m, 2H);7.20-7.14 (m 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z):(M+1)⁺. found, 233.

Step 2

Bromotrimethylsilane (15.3 mL, 0.116 mol) was added dropwise to4-fluorophenyl-phosphonic acid diethyl ester (8.95 g, 38.58 mmol)stirred in a reaction flask chilled to 0° C. The resulting solution wasallowed to warm to ambient temperature and stirred for an additionalhour. The mixture was then concentrated by rotary evaporation yieldingcrude 4-fluorophenyl-phosphonic acid bis(trimethylsilyl)ester which wasused in the next step without further purification.

Step 3

To the 4-fluorophenyl-phosphonic acid bis(trimethylsilyl)ester from Step2 was added dry methylene chloride (50 mL) and dry DMF (1 mL), followeddropwise by oxalyl chloride (11.0 mL, 126 mmol). The resulting solutionwas stirred overnight at ambient temperature. The reaction wasconcentrated by rotary evaporation to yield 10.02 g of a yellow waxysolid that was purified by distillation at reduced pressure to yield6.86 g of 4-fluorophenyl-phosphonic dichloride (32.2 mmol, 83%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.08-7.98 (m, 2H); 7.35-7.26 (m2H).

Step 4

4-Fluorophenyl-phosphonic dichloride (6.86 g, 32.2 mmol) was dissolvedin dry THF (50 mL), placed under a nitrogen atmosphere, and chilled to−70° C. To this stirred solution was added dropwise a solution of vinylmagnesium bromide in THF (80.5 mL, 1M). The resulting solution wasstirred for 90 minutes at −70° C. An aqueous solution of ammoniumchloride (500 mL, 2M) was chilled to 0° C. and stirred rapidly while thecold reaction mixture was added. The product was extracted intodichloromethane and washed with saturated aqueous sodium bicarbonatefollowed by water. The organic phase was dried with sodium sulfate,filtered, and concentrated by rotary evaporation to yield 5.214 g of4-fluoro-phenyl-divinyl-phosphine oxide (26.6 mmol, 83%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) 7.80-7.71 (m, 2H); 7.25-7.18 (m 2H);6.56-6.22 (m, 6H); ESMS (m/z): (M+1)⁺. found, 197.

Step 5

(4-Fluorophenyl)divinyl phosphine oxide (1.50 g, 7.65 mmol) andbenzylamine (1.05 mL, 9.57 mmol) were dissolved in a mixture of 100 mLof THF and 100 mL of deionized water. The reaction mixture was heated at90° C. overnight. The reaction mixture was concentrated by rotaryevaporation and the product was extracted into dichloromethane andwashed with saturated brine. The organic phase was dried with sodiumsulfate, filtered, and concentrated by rotary evaporation to yield 2.52g of crude product. Impurities were removed by passing a solution of thecrude product in ethyl acetate through a plug of silica. The product wasthen eluted from the silica with 10% methanol in ethyl acetate. Thesolvents were removed by rotary evaporation to yield 1.89 g (6.24 mmol,82%) of 1-benzyl-4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide as acolorless oil. ESMS (m/z): (M+1)⁺. found, 304.

Step 6

1-Benzyl-4-(4-fluorophenyl)-[1,4]azaphosphinane 4-oxide (from Step 5)was dissolved in ethanol (80 mL) and 40 mL of 1N aqueous HCl was added.The solution was degassed with a stream of nitrogen and then palladiumon carbon (10%, 1.0 g) was added. The mixture was hydrogenated on a Parrshaker overnight at 50 psi. The mixture was filtered through Celite andwashed with 2:1 ethanol:1N HCl and all solvents were removed underreduced pressure. The product was dissolved in ethanol and benzene wasadded, and the solvents were removed by rotary evaporation. The productwas recrystallized from ethanol to yield 1.158 g (4.64 mmol, 61%) of4-(4-fluorophenyl-[1,4]azaphosphinane 4-oxide hydrochloride as a whitecrystalline solid. ¹H NMR (400 MHz, DMSO) δ 9.10-10.10 (d, 2H);7.88-7.98 (m, 2H); 7.44-7.54 (m, 2H); 3.38-3.57 (m, 4H), 2.65-2.80 (m,2H); 2.49-2.52 (m, 2H); ESMS (m/z): (M+1)⁺. found, 214.

The free base of 4-(4-fluorophenyl-[1,4]azaphosphinane 4-oxidehydrochloride was obtained using procedures similar to those describedin Intermediate 2 and Example 3, Step 6.

Intermediate 8: 1-Methyl-1-oxo-1λ⁵-phosphinane-4-carboxylic acid

Step 1

To a 1 L round bottom flask equipped with a magnetic stir bar was addeddivinyl-methyl-phosphine oxide (10 g, 86 mmol), O,O-dibenzylmalonate (27g, 95 mmol), DMSO (400 mL), and potassium carbonate (18 g, 130 mmol).The heterogeneous mixture was headed to 75° C. After 22 hours, thereaction was complete as determined by analytical HPLC. The reaction wascooled to room temperature, poured onto ice (500 mL) and extracted intoEtOAc (3×100 mL). The organic fractions were collected, washed with 1 naqueous HCl (2×125 mL), saturated sodium bicarbonate (1×100 mL), thenbrine (3×125 mL). The organic layer was finally washed briefly with anaqueous solution of citric acid (1 n, 50 mL), dried over sodium sulfate,and concentrated to a light brown syrup. The crude product was furtherpurified by silica gel chromatography, eluting with MeOH/EtOAc (5% to10%) to provide 1-methyl-1-oxo-1λ⁵-phosphinane-4,4-dicarboxylic aciddibenzyl ester (12 g, 35%) as a clear amber colored syrup. ¹H NMR (400MHz, CDCl₃) δ ppm 7.33-7.29 (m, 6H), 7.27-7.22 (m, 4H), 5.13-5.11 (m,2H), 2.61-2.50 (m, 2H), 2.33-2.23 (m, 2H), 2.02-1.95 (m, 2H), 1.92-1.73(m, 2H), 1.45 (d, J=13 Hz, 3H); ESMS m/z. found, 423 (M+Na)⁺.

Step 2

To a 500 mL Parr flask was added1-methyl-1-oxo-1λ⁵-phosphinane-4,4-dicarboxylic acid dibenzyl ester(23.0 g, 59.7 mmol). The solid was fully dissolved in ethanol (200 mL).To the solution was added palladium on carbon (10%, 1.15 g), and theflask was charged with hydrogen gas (48 psi). The flask was agitatedwith a mechanical shaker for 2.5 hours, after which time the startingmaterial was completely consumed as determined by LC-MS. A large amountof white precipitate was present in the reaction mixture. Water (100 mL)and methanol (100 mL) was added to dissolve the precipitate, and thepalladium on carbon was removed by filtration through celite, washingwith water/methanol (1:1). The resulting filtrate was concentrated invacuo to remove most of the methanol and ethanol. The remaining waterwas removed by lyophilization to provide1-methyl-1-oxo-1λ⁵-phosphinane-4,4-dicarboxylic acid (12.68 g, 96%) as awhite free-flowing powder. ¹H NMR (400 MHz, D₂O) δ 2.40-2.20 (m, 4H),1.95-1.85 (m, 4H), 1.49 (d, J=13.3 Hz, 3H); ESMS m/z. found, 423 (221(M+1)⁺, 441 (2M+1)⁺.

Step 3

To a 50 mL microwave pressure flask equipped with a stir-bar was added1-methyl-1-oxo-1λ⁵-phosphinane-4,4-dicarboxylic acid (0.25 g, 5.7 mmol)and water (20 mL) to give a suspension. The flask was sealed and heatedto 215° C. over 60 seconds, at which point a pressure spike wasobserved. The flask was allowed to cool to room temperature then ventedto release pressure from dissolved CO₂. The resulting clear andcolorless solution was concentrated by lyophilization to provide1-methyl-1-oxo-1λ⁵-phosphinane-4-carboxylic acid in quantitative yieldas a mixture of cis/trans isomers (−2:1; identity of the favored isomernot determined). ¹H NMR (400 MHz, D₂O) δ ppm 2.6-2.4 (m, 1H), 2.2-1.6(m, 8H), 1.48 (d, J=12.9 Hz, minor isomer, 1H), 1.44 (d, J=13.7 Hz,major isomer, 2H); ESMS m/z. found, 177 (M+1)⁺, 353 (2M+1)⁺.

Intermediate 9: 1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-dicarboxylic aciddibenzyl ester

Step 1

To a 1 L round-bottom flask equipped with a magnetic stir-bar was addeddivinyl-phenyl-phosphine oxide (8.34 g, 46.8 mmol), DMSO (240 mL),dibenzylmalonate (13.31 g, 46.8 mmol), and K₂CO₃ (9.7 g, 70 mmol). Theflask was sealed with a plastic stopper and heated to 75° C. for 2hours, then cooled to 70° C. and heated an additional 14 hours. Thereaction mixture was then cooled to room temperature, poured into 1 Naqueous HCl (300 mL) and extracted into EtOAc (3×100 mL). The organiclayers were collected and washed with brine (2×100 mL), dried oversodium sulfate, and concentrated to a dark brown syrup. The crudeproduct was purified by flash chromatography, eluting with MeOH:DCM(0-20%) to give 1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-dicarboxylic aciddibenzyl ester (8.5 g, 39%) as a light brown syrup. ¹H NMR (400 MHz,CDCl₃) δ 7.48-7.43 (m, 3H), 7.39-7.37 (m, 2H), 7.28-7.19 (m, 10H), 5.12(s, 3H), 5.09 (s, 3H), 2.56-2.49 (m, 4H), 1.97-1.90 (m, 4H); ESMS m/z.found, 464 (M+1)⁺.

Step 2

To a 500 mL Parr flask was added1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5g, 18 mmol), ethanol (250 mL), and palladium on carbon (10%, 1.1 g). Theflask was charged with hydrogen (51 psi), and agitated on a mechanicalshaker. After 1 hour, the ballast was re-charged to 50 psi (from 40 psi)and shaking continued overnight (14 hours). The reaction mixture wasfiltered and the solvent removed in vacuo to provide1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-dicarboxylic acid (1.8 g, 35%) as awhite solid. ¹H NMR (400 MHz, d₆-DMSO) δ 7.9-7.4 (m, 5H), 2.6-1.4 (m,8H); ESMS m/z. found, 283 (M+1)⁺.

Step 3

To a 250 mL round-bottom flask equipped with a magnetic stir-bar wasadded 1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-dicarboxylic acid followed by 4N HCl (100 mL). The flask was equipped with a condenser and heated to avigorous reflux for 32 hours. The mixture was frozen and lyophilized togive an off white solid, which was redissolved in 1:1 water:MeCN (100mL), filtered, and lyophilized a second time to provide crude1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-carboxylic acid, which was usedwithout further purification. ¹H NMR (400 MHz, d₆-DMSO) δ 7.9-7.4 (m,5H), 2.6-1.4 (m, 9H); ESMS m/z. found, 239 (M+1)⁺.

Intermediate 10:2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acidethyl ester

Step 1

To a 1 L two-neck round bottom flask was added2,6-dichloro-3-nitrobenzonitrile (11.1 g, 51.1 mmol) followed by ethylacetate (102 mL). The flask was equipped with an internal thermometerand magnetic stir bar and cooled to 5° C. by immersion into an ice bath.Methylamine was added dropwise to the cooled reaction mixture as a 40%aqueous solution (8.9 mL, 115 mmol) with vigorous stirring. The reactionmixture was stirred for an additional 3 hours with cooling, after whichmore methylamine (1.8 mL, 23 mmol) was added. The reaction vessel wasremoved from the ice bath and stirred for an additional 1.5 hours. Tothe reaction mixture was added water (30 mL) followed immediately byhexane (45 mL) and the resulting slurry was stirred for 15 minutes. Thesolid was recovered by filtration and washed with water followed bymethanol to provide 6-chloro-2-methylamino-3-nitro-benzonitrile (10.49g, 96%) as a bright yellow solid, which was used directly withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55-8.53 (m, 1H),8.28 (d, 1H, J=9.0 Hz), 6.95 (d, 1H), J=9.0 Hz), 3.30 (d, 1H, J=5.5 Hz).

Step 2

To a 1 L two-neck round bottom flask equipped with a magnetic stir barand internal thermometer was added potassium tert-butoxide (5.0 g, 45mmol) and dimethylsulfoxide (100 mL). To the rapidly stirred suspensionwas added 2-methylacetoacetate (7.13 g, 49.5 mmol) dropwise over 5minutes. After the addition was complete the mixture was clear andslightly yellow. To the reaction mixture was then added6-chloro-2-methylamino-3-nitro-benzonitrile (8.6 g, 41 mmol) from Step 1in portions over 15 minutes. The reaction mixture immediately becamedeep red in color and the temperature rose to 40° C. The reactionmixture was stirred for 1.5 hours, then poured into a saturated solutionof NH₄Cl (100 mL). The mixture was extracted with EtOAc (3×150 mL). Theorganic layers were combined and washed with brine (3×100 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder vacuum to produce a deep red oil. Methanol (40 mL) was added andthe mixture was stirred for 1.5 hours with cooling over an ice bath. Theresulting precipitate was recovered by filtration and washed with coldmethanol to provide2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acidethyl ester (7.13 g, 40.6%) as a yellow solid, which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (d, 1H, J=9.0Hz), 8.10-8.05 (m, 1H), 6.64 (d, 1H, J=9.0 Hz), 4.28-4.19 (m, 2H), 3.17(d, 3H, J=5.5 Hz), 2.36 (s, 3H), 1.81 (s, 3H), 1.22 (t, 3H, J=7.0 Hz).

Step 3

To a 500 mL Parr pressure flask was added2-(2-cyano-3-methylamino-4-nitro-phenyl)-2-methyl-3-oxo-butyric acidethyl ester (7.13 g, 16.5 mmol) as a solution in EtOAc (50 mL) followedby 10% palladium on carbon (1.0 g). The flask was purged under vacuum,then charged with hydrogen gas (50 psi). The flask was agitated at roomtemperature for while open to the ballast (caution: potential exotherm).After 8 hours, TLC analysis indicated that all starting material hasbeen consumed. The reaction mixture was filtered through a pad of celiteand washed with EtOAc. The resulting solution was concentrated toprovide 2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyricacid ethyl ester (5.11 g, 77%) as a gray solid, which was used withoutfurther purification. ¹H NMR (400 MHz, d₆-DMSO) δ 6.70 (d, J=8.2 Hz,1H), 6.33 (d, J=8.2 Hz, 1H), 6.17 (s, 2H), 4.90 (q, J₁=5.1 Hz, J₂=10.6Hz, 1H), 4.21-4.15 (m, 2H), 2.95 (d, J=5.5 Hz, 2H), 2.22 (s, 3H), 1.66(s, 3H), 1.2 (t, J=7.0 Hz, 3H).

Intermediate 11: Acetic acid1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allylester

Step 1

2,6-Dichlorophenyl isothiocyanate (3.46 g, 17.0 mmol), THF (100 mL), and2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acidethyl ester (4.91 g, 17.0 mmol), were added to a 250 mL round bottomflask equipped with a magnetic stir bar and the reaction was stirred atroom temperature. After 2 hours, mercuric oxide (4.04 g, 18.7 mmol) wasadded and the reaction stirred for an additional 14 h. The resultantbrown slurry was filtered through celite and washed with THF. Thefiltrate was concentrated and the residue triturated with diethyl etherto provide2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (4.2 g, 54%) as a gray solid, which was used withoutfurther purification.

Step 2

A 25 mL round bottom flask was charged with2-[4-cyano-2-(2,6-dichloro-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (0.258 g, 0.562 mmol) and a stir bar. Water (3 mL),glacial acetic acid (3 mL) and concentrated sulfuric acid (3 mL) werecombined and added to the round bottom flask while still hot (60° C.).The flask was sealed with a plastic stopper and heated in an oil bath at100° C. After 2 hours, the flask was removed from the oil bath andstirred at room temperature overnight. The clear solution was thenpoured onto ice and neutralized with concentrated ammonium hydroxide.The resulting precipitate was recovered by filtration, resuspended inmethanol and filtered. The resulting solid was washed with methanoluntil the filtrate was colorless to provide2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.106 g, 46%) as a light gray solid, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ 11.47 (s, 1H), 7.78-7.68(m, 4H), 7.59 (t, 1H, J=8.6 Hz), 4.28 (2, 3H), 2.31 (s, 3H), 2.22 (s,3H); ESMS (m/z). found, 387.

Step 3

To a 200 mL round bottom flask equipped with a stir bar was added2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(2.4 g, 6.2 mmol), selenium dioxide (2.0 g, 18 mmol) and dioxane (150mL). The flask was fitted with a condenser and heated to reflux for 4.5h. The reaction was then removed from heat and allowed to cool to roomtemperature. The slightly opaque solution was filtered through celiteand washed with dichloromethane:methanol (9:1). The solution wasconcentrated and the resulting residue triturated with dichloromethaneto produce2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(1.8 g, 72%) as a brownish yellow solid, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ 10.65 (s, 1H), 10.24 (s,1H), 7.96 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.70 (d, 2H, J=7.8Hz), 7.49 (d, 2H, J=7.8 Hz), 4.15 (s, 3H), 2.70 (s, 3H); ESMS (m/z).found, 401.

Step 4

To a 50 mL round bottom flask equipped with a stir bar was added2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(0.415 g, 1.03 mmol) and THF (12 mL). The reaction mixture was cooled to−78° C. To the stirred suspension was added vinylmagnesium bromide (5mL, 1 M in THF, 5 mmol) in one portion. The solution was allowed togradually warm to −30° C. over 1 h. Additional vinylmagnesium bromide (3mL, 1M in THF, 3 mmol) was added and the reaction mixture was furtherwarmed to 0° C. over 1.5 h. The cold reaction mixture was poured intosaturated aqueous ammonium chloride (50 mL) and extracted with EtOAc(3×50 mL). The organic fractions were collected, washed with brine (3×25mL) and concentrated. The resulting solid was further purified by flashchromatography, eluting with EtOAc:Hexane (0-100%) to give2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.175 g, 40%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ10.43 (s, 1H), 7.77-7.75 (m, 4H), 7.59 (t, 1H, J=8.6 Hz), 6.06-5.98 (m,1H) 5.42 (app d, 1H, J=5.5 Hz), 5.32 (app d, 1H, J=17.2 Hz), 5.16 (appd, 1H, J=10.2 Hz), 4.26 (s, 3H), 2.27 (s, 3H); ESMS (m/z). found, 429.

Step 5

To a 100 mL round bottom flask equipped with a magnetic stir bar wasadded2-(2,6-dichloro-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.175 g, 0.409 mmol), THF (5 mL), triethylamine (60 μL, 0.43 mmol) andacetic anhydride (1 mL). To the stirring suspension was then addedN,N-dimethylaminopyridine (2 mg, 0.016 mmol). The reaction mixturebecame clear in 1 minute, and TLC analysis indicated that all startingmaterial had been consumed. The reaction mixture was concentrated invacuo and the residue was further purified by silica gel chromatography,eluting with methanol:dichloromethane (0-10%) to provide acetic acid1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allylester (0.168 g, 87%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆+TFA) δ 11.42 (s, 1H), 7.80-7.76 (m, 4H), 7.57 (t, 1H, J=8.2 Hz),6.34 (d, 1H, J=6.3 Hz), 6.21-6.13 (m, 1H), 5.41 (d, 1H, J=17.2 Hz), 5.33(d, 1H, J=10.2 Hz), 4.25 (s, 3H), 2.33 (s, 3H), 2.12 (s, 3H); ESMS(m/z). found, 471.

Intermediate 12:7-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

Step 1

To a 50 mL round bottom flask equipped with a magnetic stir bar wasadded Pd₂(dba)₃ (38 mg, 42 μmol), triphenylphosphine (52 mg, 200 μmol)and THF (6.6 mL). The resulting solution was stirred under nitrogen for20 minutes followed by the addition of acetic acid1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allylester (0.288 mg, 0.664 mmol). The resulting red solution was stirred for20 minutes, then sodium azide (47 mg, 0.72 mmol) was added as a solutionin water (0.6 mL). The flask was sealed with a plastic cap and heated to60° C. for 3 hours. The reaction mixture was cooled to room temperatureand triphenylphosphine (165 mg, 0.63 mmol) was added. After stirring atroom temperature for 7 hours, ammonium hydroxide was added (0.7 mL) andthe reaction was stirred for 12 additional hours. The reaction mixturewas diluted with ethyl acetate (50 mL) and the solution dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productwas purified by flash chromatography, eluting with MeOH:HCCl₃ (10-40%)to give7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.¹H NMR (400 MHz, d₆-DMSO) δ 11.24 (s, 1H), 10.62 (s, 1H), 8.1-8.0 (m,2H), 7.77 (d, J=9 Hz, 1H), 7.71 (d, J=9 Hz, 1H), 7.6-7.5 (m, 1H),6.6-6.45 (m, 2H), 4.18 (s, 3H), 3.75-3.65 (m, 2H), 2.36 (s, 3H), 2.30(s, 3H); ESMS m/z. found, 392 (M+1)⁺.

Example 12-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 1)

Step 1

To a glass scintillation vial was added2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acidethyl ester (0.247 g, 0.854 mmol), followed by THF (5 mL) and a magneticstir bar. To the resulting solution was added4-fluoro-1-isothiocyanato-2-methyl-benzene (0.191 g, 1.14 mmol) and thesolution was stirred at room temperature for 48 h. To the solution wasthen added mercuric oxide (0.222 g, 1.02 mmol), and stirring wascontinued at room temperature for 24 h. The brown suspension was thenfiltered through a ½ inch thick pad of silica, washed with THF, andconcentrated to dryness. The resulting deep red solid was furtherpurified by silica gel chromatography, eluting with ethyl acetate:hexane(0%-100%) to provide2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (0.204 g, 56%) as a deep red solid. ESMS (m/z): (M+1)⁺.found, 423.

Step 2

To a glass scintillation vial equipped with a magnetic stir bar wasadded2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (0.204 g, 0.483 mmol). A freshly prepared mixture ofH₂O (3.3 mL), glacial acetic acid (3.3 mL), and concentrated sulfuricacid (3.3 mL) at 60° C. was added to the vial. The vial was sealed witha screw cap and heated to 100° C. in a heating block. After 2.5 hours,the vial was allowed to cool to room temperature and stirred for anadditional 12 h. The reaction mixture was then poured onto ice andneutralized by addition of concentrated ammonium hydroxide. Theresulting precipitate was recovered by filtration and further purifiedby trituration with methanol to provide2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.1188 g, 70 as a light gray solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ11.43 (br s, 1H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H,J₁=5.5 Hz, J₂=8.6 Hz), 7.37 (dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.27 (td,1H, J₁=3.1 Hz, J₂=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s,3H); ESMS (m/z). found, 351.

Step 3

To a 200 mL round-bottom flask equipped with a magnetic stir bar wasadded2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(1.3 g, 3.7 mmol) selenium dioxide (1.23 g, 11.0 mmol) and dioxane (100mL). The flask was fitted with a reflux condenser and heated to 100° C.in an oil bath for 5 h. The flask was then cooled to room temperatureand the mixture filtered through a plug of celite, washing with 10%MeOH/DCM. The filtrate was concentrated to dryness and the resultingbrown solid further purified by trituration with cold DCM to give2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(1.11 g, 82%) as a red-yellow solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35(dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.26 (td, 1H, J₁=3.1 Hz, J₂=8.6 Hz),4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z). found, 365.

Step 4

To a 100 mL round-bottom flask equipped with a magnetic stir bar wasadded give2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(0.750 g, 2.06 mmol) followed by THF (20 mL). The suspension was cooledto −78° C., then vinylmagnesium bromide (16.5 mmol, 1.0 M in THF) wasadded over 5 minutes. The reaction mixture was allowed to warm to −10°C. over 2.5 hours, after which time all material was fully dissolved.The cold reaction mixture was poured into saturate aqueous ammoniumchloride (100 mL) and extracted with ethyl acetate (3×30 mL). Theorganic fractions were collected, washed with brine (1×50 mL), driedover sodium sulfate, and concentrated in vacuo to provide2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.680 g, 84%) as an orange-yellow solid, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ 10.52 (br s, 1H), 10.38(br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35(dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.24 (td, 1H, J₁=9.1 Hz, J₂=11.7 Hz),6.02 (ddd, 1H, J₁=5.9 Hz, J₂=10.6 Hz, J₃=17.2 Hz), 5.41 (app d, 1H,J=5.5 Hz), 5.33 (dt, 1H, J₁=1.6 Hz, J₂=17.2 Hz), 5.17 (dt, 1H, J₁=1.2Hz, J₂=10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z).found, 393.

Step 5

To a 25 mL round-bottom flask equipped with a magnetic stir bar wasadded2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(0.65 g, 1.7 mmol), THF (5 mL), triethylamine (0.52 g, 5.1 mmol) andacetic anhydride (0.22 g, 2.2 mmol). To the stirred suspension was thenadded DMAP (0.002 g, 0.02 mmol). After 1 hour, all reation componentswere fully dissolved and the reaction was complete as determined by TLCanalysis. To the reaction mixture was added saturated aqueous ammoniumchloride (20 mL) and the solution was extracted with ethyl acetate (2×20mL). The organic fractions were collected, washed with brine (1×20 mL),dried over sodium sulfate, and concentrated in vacuo. The crude productwas further purified by silica gel chromatography, eluting with 2%methanol:DCM to provide acetic acid1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allylester (0.404 g, 55%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δppm 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d,1H, J=8.6 Hz), 7.56 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.37-7.34 (m, 3H),7.25 (td, 1H, J₁=2.7 Hz, J₂=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17(ddd, 1H, J₁=6.3 Hz, J₂=10.2 Hz, J₃=16.8 Hz), 5.41 (app d, 1H, J=17.2Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s,3H); ESMS (m/z). found, 435.

Step 6

To a glass scintillation vial was added 4-methyl-[1,4]azaphosphinane4-oxide (100 mg, 0.75 mmol). To a separate glass vial was addedtris(dibenzylacetone)dipalladium (28 mg, 0.031 mmol), triphenylphosphine(30 mg, 0.12 mmol), and THF (2.5 mL). The resulting solution was stirredfor 20 minutes, then acetic acid1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allylester (0.270 g, 0.621 mmol) was added as a solution in THF (7.0 mL),followed by TEA (0.90 mL, 12.2 mmol). Of the resulting solution, 2.4 mL(0.15 mmol total allylic acetate) was transferred to the vial containing4-methyl-[1,4]azaphosphinane 4-oxide. The solution was stirred at roomtemperature for 20 h. The solvent was removed in vacuo and the resultingsolid redissolved in MeCN (2 mL) and DMSO (2 mL). The solution wasfiltered, then purified directly by preperative reverse-phase HPLC (0%to 100% MeCN:H₂O+0.1% formic acid) to give2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-methyl-4-oxo-4λ5[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(32 mg, 42%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ11.33 (br s, 1H), 10.68 (br s, 1H), 7.79 (d, 1H, J=8.6 Hz), 7.72 (d, 1H,J=8.6 Hz), 7.56 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35 (dd, 1H, J₁=3.9 Hz,J₂=9.8 Hz), 7.25 (td, 1H, J₁=3.1 Hz, J₂=8.6 Hz), 7.19-7.15 (m, 2H),6.54-6.48 (m, 1H), 4.18 (s, 3H), 4.10-4.00 (br s, 2H), 3.80-3.30 (br m,4H), 3.16 (s, 3H), 2.36 (s, 3H), 3.31 (s, 3H), 2.30-2.10 (br m, 4H),1.7-1.6 (br m, 3H); ESMS (m/z). found, 508.

Example 22-(2,6-dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 5)

2-(2,6-Dichloro-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ^(5[)1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared following the procedure of Example 1 form acetic acid1-[2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allylester and 4-phenyl-[1,4]azaphosphinane 4-oxide. ¹H NMR (400 MHz,DMSO-d₆+TFA) δ 11.38 (br s, 1H), 10.71 (br s, 1H), 7.90-7.60 (m, 9H),7.56 (t, 1H, J=7.8 Hz), 7.22 (br d, 1H, J=15.3 Hz), 7.70-6.40 (br m,1H), 4.23 (s, 3H), 4.18 (br m, 2H), 4.00-4.15 (br m, 4H), 2.60-2.40 (brn, 4H), 2.39 (s, 1H); ESMS (m/z). found, 606 (M+1)⁺.

Example 32-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-oneHCl (Compound 3)

Step 1

To a 250 mL round-bottom flask was added2-(4-amino-2-cyano-3-methylamino-phenyl)-2-methyl-3-oxo-butyric acidethyl ester (10.8 g, 37.4 mmol), DMAP (228 mg, 1.87 mmole), and THF (80mL). The solution was stirred with gentle heating until all the materialwas fully dissolved. The reaction mixture was then concentrated undervacuum to achieve a final volume of approximately 20 mL. After coolingto room temperature, 4-fluoro-1-isothiocyanato-2-methyl-benzene (9.36 g,56.0 mmole) was added in one portion, and stirring was continued at roomtemperature for 12 hours, after which time all the diamine had beenconverted to the corresponding thiourea as determined by TLC analysis.To the reaction mixture was then added mercuric oxide (12.15 g, 56mmole) and the resulting slurry stirred at room temperature. The slurryrapidly became black, indicating the formation of mercuric sulfide.After 1 hour, the reaction was complete as determined by TLC analysis.Silica gel was added to the mixture and the resulting thick slurry wasfiltered through a pad of celite, washing with several volumes of EtOAc.The clear filtrate was concentrated to produce a dark gray solid. To thesolid was added diethylether, and the insoluble material was isolated byfiltration to provide2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (8.25 g, 52%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71 (s, 1H), 7.46-7.42 (m, 2H), 7.14 (dd, 1H, J₁=3.1 Hz,J₂=9.8 Hz), 7.06 (td, 1H, J₁=2.7 Hz, J₂=8.6 Hz), 6.87 (d, 1H, J=8.6 Hz),4.28-4.19 (m, 2H), 3.95 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.81 (s,3H), 1.23 (t, 3H, J=7.4 Hz); ESMS (m/z): 423 (M+1)⁺.

Step 2

To a 500 mL round-bottom flask equipped with a magnetic stir-bar wasadded2-[4-cyano-2-(4-fluoro-2-methyl-phenylamino)-3-methyl-3H-benzoimidazol-5-yl]-2-methyl-3-oxo-butyricacid ethyl ester (8.25 g, 1.95 mmole), followed by a freshly preparedmixture of water (25 mL), acetic acid (25 mL), and concentrated sulfuricacid (25 mL) at 60° C. The flask was fitted with a reflux condenser andheated to a bath temperature of 100° C. under a nitrogen atmosphere.After 5 hours, the reaction was allowed to cool to room temperature, andstirred for an additional 14 hours. The mixture was then poured onto iceand brought to a slightly basic pH by careful addition of concentratedammonium hydroxide, while maintaining a temperature of less than 15° C.The resulting precipitate was isolated by filtration, and washed withseveral volumes of water. The solid was then slurried in methanol for 1hour, and filtered. The isolated solid was washed with cold methanoluntil the filtrate was colorless, to provide2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(6.11 g, 89%) as a light gray solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ11.43 (br s, 1H), 10.49 (br s, 1H), 7.70-7.65 (m, 2H), 7.57 (dd, 1H,J₁=5.5 Hz, J₂=8.6 Hz), 7.37 (dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.27 (td,1H, J₁=3.1 Hz, J₂=11.7 Hz), 4.23 (s, 3H), 2.32 (app s, 6H), 2.23 (s,3H); ESMS (m/z): 351 (M+1)⁺.

Step 3

To a 1 L round-bottom flask equipped with a magnetic stir-bar was addeddioxane (500 mL) and water (16.5 mL). The solution was heated to 55° C.,and selenium dioxide (8.6 g, 77 mmole) was added. The mixture wasstirred at 55° C. for one hour, over which time all the selenium dioxidehad dissolved. To the solution was then added2-(4-fluoro-2-methyl-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one.The flask was fitted with a reflux condenser and the resulting slurryheated to a bath temperature of 115° C. After 18 hours, additionalselenium dioxide (4.0 g, 36 mmole) was added and stirring continued for6 hours. The reaction mixture was dark red, with gray metallic seleniumlining the sides of the flask. The reaction mixture was cooled to roomtemperature then filtered through a pad of celite and washed with 10%MeOH/DCM. The filtrate was concentrated in vacuo to produce a gummy redsolid. Methanol (50 mL) was added, and the mixture stirred over an icebath, during which time a flocculent yellow precipitate formed. Thesolid was isolated by filtration, and washed sparingly with coldmethanol to give2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(3.90 g, 61%) as a bright yellow solid. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ10.80 (br s, 1H), 10.70 (br s, 1H), 10.25 (s, 1H), 8.02 (d, 1H, J=8.8Hz), 7.80 (d, 1H, J=8.8 Hz), 7.57 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35(dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.26 (td, 1H, J₁=3.1 Hz, J₂=8.6 Hz),4.14 (s, 3H), 2.69 (s, 3H), 2.31 (s, 3H); ESMS (m/z): 365 (M+1)⁺.

Step 4

To a 1 L 3-neck round-bottom flask equipped with a magnetic stir-bar wasadded2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde(7.96 g, 21.9 mmole) and THF (260 mL). The resulting slurry was cooledto −78° C., and vinylmagnesium bromide (175 mL, 1.0 M in THF) was addeddropwise over 30 minutes. The mixture was stirred at −78° C. for 2hours, then warmed to −10° C. over 30 minutes and maintained at −10° C.for an additional 2 hours. The reaction was then quenched by addition ofsaturated aqueous ammonium chloride (200 mL), and extracted into EtOAc(2×200 mL). The organic layers were collected, washed with brine (2×100mL), dried over sodium sulfate, and concentrated in vacuo to provide2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(7.8 g, 91%) as an orange-yellow solid, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆+TFA) δ 10.52 (br s, 1H), 10.38(br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35(dd, 1H, J₁=3.1 Hz, J₂=9.8 Hz), 7.24 (td, 1H, J₁=9.1 Hz, J₂=11.7 Hz),6.02 (ddd, 1H, J₁=5.9 Hz, J₂=10.6 Hz, J₃=17.2 Hz), 5.41 (app d, 1H,J=5.5 Hz), 5.33 (dt, 1H, J₁=1.6 Hz, J₂=17.2 Hz), 5.17 (dt, 1H, J₁=1.2Hz, J₂=10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z):393 (M+1)⁺.

Step 5

To a 500 mL round-bottom flask equipped with a magnetic stir-bar wasadded2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(7.8 g, 20 mmole), DCM (100 mL), TEA (3.0 g, 30 mmole), and DMAP (25 mg,0.2 mmole). To the rapidly stirred suspension at room temperature wasadded acetic anhydride (2.3 g, 23 mmole). The reaction was completeafter 10 minutes as determined by TLC analysis. The mixture was dilutedwith DCM (100 mL), and washed with saturated aqueous ammonium chloride.The aqueous layer was back-extracted with additional DCM (100 mL). Thecombined organic fractions were washed with brine (2×100 mL), dried oversodium sulfate, and concentrated in vacuo to give an amorphous orangesolid. The crude product was re-dissolved in 5% MeOH/DCM (65 mL). To thestirred solution was added diethyl ether (200 mL), which resulted in theformation of a bright yellow precipitate. The stirred suspension wascooled over a salt/ice bath to −5° C., then filtered to recover thesolids. The solids were washed sparingly with diethyl ether andcollected to provide acetic acid1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]allylester (6.94 g, 80.4%) as a yellow powder. ¹H NMR (400 MHz, DMSO-d₆+TFA)δ 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d,1H, J=8.6 Hz), 7.56 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.37-7.34 (m, 3H),7.25 (td, 1H, J₁=2.7 Hz, J₂=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17(ddd, 1H, J₁=6.3 Hz, J₂=10.2 Hz, J₃=16.8 Hz), 5.41 (app d, 1H, J=17.2Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s,3H); ESMS (m/z): 435 (M+1)⁺.

Step 6

To a 500 mL round-bottom flask was added 4-phenyl-[1,4]azaphosphinane4-oxide hydrochloride salt (5.91 g, 25.6 mmole), MP-carbonate resin (20g, 2.9 mmole/g), and water (200 mL). The flask was sealed with a plasticstopper and placed on an orbital shaker for 12 hours. The resin was thenremoved by filtration with though a glass frit, and washed with water(40 mL) to provide 4-phenyl-[1,4]azaphosphinane 4-oxide free-base as anaqueous solution.

Step 7

To a 500 mL 3-neck round-bottom flask equipped with a magnetic stir-barand internal thermometer was added Pd₂(dba)₃.HCCl₃ (0.476 g, 0.46mmole), triphenylphosphine (0.383 g, 1.5 mmol), and THF (100 mL). Theresulting wine-red solution was stirred under a nitrogen atmosphere for30 minutes. To the stirred solution was then added solid acetic acid1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allylester (4.0 g, 9.2 mmole) in a single portion. An aqueous solution of4-phenyl-[1,4]azaphosphinane 4-oxide free-base (200 mL, 0.106 M) wasnext added to the stirring solution over 3 minutes via an additionfunnel. The temperature of the reaction immediately rose from 24° C. to29.5° C. and maintained this temperature for about 20 minutes. After 1hour, the reaction mixture had cooled to room temperature and a yellowprecipitate had formed. The precipitate was isolated by filtration andwashed with water followed by diethyl ether. The filter cake wasre-dissolved in methanol (150 mL) and cooled over an ice bath. To thechilled solution with rapid stirring was added anhydrous HCl (10 mL,1.25 M in methanol). The solution was then poured into a flaskcontaining diethyl ether (600 mL) with stirring. Pentane (100 mL) wasadded, followed by additional anhydrous HCl (20 mL, 1.25 M in methanol).The resulting solution was decanted, leaving crude product as a gum onthe sides of the flask. This material was re-dissolved in methanol (100mL). Into the stirred solution was poured diethyl ether, resulting in ayellow flocculent precipitate. This was recovered by filtration andwashed with diethyl ether to give2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ⁵-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-oneHCl salt (2.9 g, 52%). ¹H NMR (400 MHz, CD₃OD) δ 7.96-7.89 (m, 2H), 7.89(d, 1H, J=9.0 Hz), 7.73 (d, 1H, J=9.0 Hz), 7.71-7.65 (m, 1H), 7.66-7.61(m, 2H), 7.51 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.32 (d, 1H, J=15.7 Hz),7.26 (dd, 1H, J₁=3.1 Hz, J₂=9.4 Hz), 7.16 (td, 1H, J₁=3.1 Hz, J₂=8.6Hz), 6.56-6.48 (m, 1H), 4.26 (s, 3H), 4.19 (d, 2H, J=7.0 Hz), 4.2-3.8(br m, 2H), 3.8-3.6 (br m, 2H), 3.0-2.9 (br m, 2H), 2.47 (s, 3H), 2.37(s, 3H), 2.5-2.3 (br m, 2H); ESMS m/z 569.7 (MH+).

Example 42-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 12)

Proceeding as above for Example3,2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(4-fluorophenylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared by replacing 4-methyl-[1,4]azaphosphinane 4-oxide with4-(4-fluorophenylmethyl)-[1,4]azaphosphinane 4-oxide. ¹H NMR (400 MHz,DMSO-d₆+TFA) δ 11.32 (br s, 1H), 10.62 (br s, 1H), 7.79 (d, 1H, J=9.2Hz), 7.72 (d, 1H, J=9.2 Hz), 7.56 (dd, 1H, J₁=6.0 Hz, J₂=8.8 Hz),7.37-7.28 (m, 3H), 7.25 (dt, 1H, J₁=2.8 Hz, J₂=8.8 Hz), 7.23-7.14 (m,3H), 6.48 (dt, 1H, J₁=7.2 Hz, J₂=14.8 Hz), 4.17 (s, 3H), 4.07 (d, 2H,J=6.8 Hz), 3.8-3.6 (br m, 2H), 3.6-3.4 (br m, 4H), 2.36 (s, 3H), 2.30(s, 3H), 2.4-2.0 (br m, 4H); ESMS (m/z). found, 602.1 (M+1)⁺.

Example 52-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 13)

Proceeding as above for Example3,2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropylmethyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared by replacing 4-methyl-[1,4]azaphosphinane 4-oxide with4-cyclopropylmethyl-[1,4]azaphosphinane 4-oxide. ¹H NMR (400 MHz,DMSO-d₆+TFA) δ 11.08 (br s, 1H), 10.70 (s, 1H), 7.79 (d, 1H, J=8.8 Hz),7.72 (d, 1H, J=8.8 Hz), 7.55 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.35 (dd,1H, J₁=2.7 Hz, J₂=9.8 Hz), 7.25 (td, 1H, J₁=3.1 Hz, J₂=8.6 Hz),7.30-7.10 (br m, 1H), 6.6-6.45 (br m, 1H), 4.18 (s, 3H), 4.10-4.00 (brm, 2H), 3.80-3.65 (br m, 2H), 3.60-3.45 (br m, 1H), 3.45-3.30 (br m,1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.50-1.70 (m, 6H), 1.0-0.70 (br m, 1H),0.56 (d, 2H, J=7.4 Hz), 0.23 (s, 2H); ESMS (m/z). found, 548 (M+1)⁺.

Example 62-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4λ⁵-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 14)

Proceeding as above for Example3,2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[4-(cyclopropyl)-4-oxo-4%-[1,4]azaphosphinan-1-yl]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared by replacing 4-methyl-[1,4]azaphosphinane 4-oxide with4-cyclopropyl-[1,4]azaphosphinane 4-oxide. ¹H NMR (400 MHz, DMSO-d₆+TFA)δ 11.37 (br s, 1H), 10.63 (s, 1H), 10.49 (br s, 1H), 7.80 (d, 1H, J=8.8Hz), 7.72 (d, 1H, J=8.8 Hz), 7.56 (dd, 1H, J₁=5.5 Hz, J₂=8.6 Hz), 7.36(dd, 1H, J₁=2.7 Hz, J₂=7.8 Hz), 7.26 (td, 1H, J₁=2.7 Hz, J₂=8.2 Hz),7.18 (br d, 1H, 15.3 Hz), 6.60-6.50 (br m, 1H), 4.18 (s, 3H), 4.15-4.05(br m, 2H), 4.00-3.40 (br m, 4H), 2.37 (s, 3H), 2.30 (s, 3H), 2.50-2.10(br m, 4H), 1.50-1.00 (br m, 1H), 0.90-0.82 (br m, 2H), 0.81-0.70 (br m,2H); ESMS (m/z). found, 534 (M+1)⁺.

Example 72-(4-fluoro-2-methyl-phenylamino)-7-[3-(4-methanesulfonyl-piperazin-1-yl)-propenyl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 24)

Proceeding as above for Example3,2-(4-fluoro-2-methyl-phenylamino)-7-[3-(4-methanesulfonyl-piperazin-1-yl)-propenyl]-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared by replacing 4-phenyl-[1,4]azaphosphinane 4-oxidehydrochloride with methansulfonylpiperazine. ¹H NMR (400 MHz, DMSO-d⁶)(free base) δ 10.78 (1H, s); 8.41 (1H, m); 7.69 (d, 1H, J=9.0 Hz);7.7-7.66 (1H, m); 7.5 (1H, J=9 Hz); 7.07 (1H, m); 7.02 (1H, m); 6.82(1H, d); 6.5 (1H, m) 14.08 (3H, s); 3.26 (2H, m); 3.19 (4H, m); 2.92(3H, s); 2.59 (4H, m); 2.37 (3H, s); 2.26 (3H, s). ESMS m/z 539 (MH+).

Example 82-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 15)

Step 1

To scintillation vial with a magnetic stir-bar was added7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(68 mg, 173 μmol), followed by dimethylformamide (DMF) (1.0 mL) andtriethylamine (TEA) (0.25 mL). To a separate scintillation vial wasadded 1-methyl-1-oxo-1λ⁵-phosphinane-4-carboxylic acid (130 mg, 0.74mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol), and DMF(2.0 mL), followed by TEA (0.25 mL). The solution was sonicated untilmost of the solids were dissolved. A solution of the activated ester(1.0 mL, or roughly half) was transferred to the solution of amine andstirred for 2.5 hours at room temperature, after which time the startingmaterial was completely consumed as determined by LC-MS. The reactionmixture was quenched by addition of water (0.5 mL), then acidified withTFA. The mixture was filtered (syringe membrane filter) and purifieddirectly by reverse-phase HPLC to provide2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(24.9 mg, 26%) as a mixture of cis/trans isomers. ¹H NMR (400 MHz,d₆-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21-8.17 (m, 1H), 7.74 (d,J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.55 (dd, J₁=5.9 Hz, J₂=9.0 Hz,1H), 7.27 (td, J₁=2.7 Hz, J₂=8.6 Hz, 1H), 6.66 (d, J=15 Hz, 1H),6.55-6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s,3H), 2.35-2.30 (m, 1H), 2.08-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.52-1.47(m, 3H); ESMS m/z. found, 550 (M+1)⁺.

Example 92-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(trans-1-phenyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 16) and2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(cis-1-phenyl-1-oxo-phosphinan-4-yl)carbonylamino]propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 17)

To a scintillation vial was added7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(70 mg, 180 μmol), DMF (2.0 mL), and TEA (110 mg, 1.1 mmol). To aseparate vial was added crude1-oxo-1-phenyl-1λ⁵-phosphinane-4,4-carboxylic acid (64 mg, 270 μmol),HATU (108 mg, 284 μmol), and DMF (2.0 mL). Once the solution of activateester had fully dissolved, the entire volume was transferred to thesolution of amine. The reaction mixture was stirred at room temperaturefor 2 hours, then quenched by addition of saturated aqueous ammoniumchloride solution (10 mL). The mixture was extracted with EtOAc (3×10mL), washed with brine, dried over sodium sulfate, and concentrated invacuo.

The crude material was further purified by flash chromatography, elutingwith MeOH:DCM (5-25%) to provide1-oxo-1-phenyl-1λ⁵-phosphinane-4-carboxylic acid{3-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl}-amideas two chromatographically distinct geometric isomers (12.7 mg of thefirst eluting isomer and 10.5 mg of the second eluting isomer, 21%combined yield). The first eluting isomer: ¹H NMR (400 MHz, d₆-DMSO+TFA)δ 11.09 (s, 1H), 10.56 (s, 1H), 8.21 (t, J=6.3 Hz, 1H), 7.83-7.81 (m,2H), 7.73 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.61-7.53 (m, 4H),7.36-7.33 (m, 1H), 7.25 (td, J₁=3.1 Hz, J₂=8.2 Hz, 1H), 6.63 (d, J=16Hz, 1H), 6.47 (dt, J₁=5.1 Hz, J₂=16 Hz, 1H), 4.18 (s, 3H), 3.9-3.86 (m,2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.7-1.9 (m, 7H), 1.7-1.6 (2H); ESMSm/z. found, 612 (M+1)⁺. The second eluting isomer: ¹H NMR (400 MHz,d₆-DMSO+TFA) δ 11.16 (s, 1H), 10.57 (s, 1H), 8.25 (t, J=5.8 Hz, 1H),7.87-7.82 (m, 1H), 7.77 (d, J=9 Hz, 1H), 7.71 (d, J=9 Hz, 1H), 7.62-7.5(m, 4H), 7.38-7.32 (m, 2H), 7.28 (td, J₁=3.1 Hz, J₂=8.6 Hz, 1H), 6.76(d, J=16 Hz, 1H), 6.6-6.5 (m, 1H), 4.20 (s, 3H), 4.0-3.9 (m, 2H), 2.35(s, 3H), 2.33 (s, 3H), 2.37-2.29 (m, 1H), 2.11-2.00 (m, 8H); ESMS m/z.found, 612 (M+1)⁺.

Example 102-(4-Fluoro-2-methylphenylamino)-7-{3-[4-(4-fluorophenyl)-piperazin-1-yl]-propenyl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one(Compound 30)

2-(4-Fluoro-2-methylphenylamino)-7-{3-[4-(4-fluorophenyl)-piperazin-1-yl]-propenyl}-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-onewas prepared following the procedure in Example 3, but replacing4-phenyl-[1,4]azaphosphinane 4-oxide with 4-fluorophenylpiperazine. ¹HNMR (400 MHz DMSO-d⁶) (free base) δ ppm 10.78 (1H, s); 8.4 (1H, s); 7.67(1H, d); 7.58 (1H, dd); 7.45 (1H, d); 7.07 (1H, m); 7.02 (2H, m); 6.95(2H, m); 6.9 (1H, d); 6.56 (1H, td); 4.05 (3H, s): 3.23 (2H, d); 3.1(4H, br. s); 2.61 (4H, br. s); 2.36 (3H, s); 2.23 (3H, s). ESMS m/z 539(MH+). 555.2.

Example 11 Inhibitory Activity Against Kinases: Enzyme Assays andCellular Assays

Suitable in vitro assays for measuring kinase activity and theinhibition thereof by compounds are known (e.g., see Kuzmic et al. Anal.Biochem. 2000, 286, 45-50).

The following protocol represents an assay for determination ofinhibition of kinases under physiological conditions (pH 7.4). Kinaseactivity was determined using a time-resolved fluorescence resonanceenergy transfer (TR-FRET) methodology. Measurements were performed in areaction volume of 50 μL using 96-well assay plates. Kinase enzyme,inhibitor, ATP (at the Km for the kinase), and 1 μM peptide substrate(Biotin-AVLESEEELYSSARQ-NH2) were incubated in a reaction buffercomposed of 20 mM Tris, 50 mM NaCl, MgCl2 (5-25 mM depending on thekinase), 1 mM DTT, 0.1 mM EDTA, 0.01% bovine serum albumin, 0.005%Tween-20, and 10% DMSO at pH 7.4 for one hour. The reaction was quenchedby the addition of 1.2 equivalents of EDTA (relative to Mg2+) in 25 μLof 1× Lance buffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) andEu-labeled p-Tyr100 antibody (Perkin-Elmer) in 1× Lance buffer wereadded in a 25 μL volume to give final concentrations of 100 nM and 2.5nM, respectively, and the mixture was allowed to incubate for one hour.The TR-FRET signal was measured on a multimode plate reader with anexcitation wavelength of 330 nm and detection wavelengths of 615 nm and665 nm. Activity was determined by the ratio of the fluorescence at 665nm to that at 615 nm. For each compound, enzyme activity was measured atvarious concentrations of compound. Negative control reactions wereperformed in the absence of inhibitor in replicates of six, and twono-enzyme controls were used to determine baseline fluorescence levelsInhibition constants were obtained using the program BatchKi (Kuzmic etal. Anal. Biochem. 2000, 286, 45-50). IC50s were obtained according tothis equation: IC50={Ki(app)/(1+[ATP]/KmATP)}+[E]total/2; for allkinases, [ATP]=KmATP, [Btk]total=0.5 nM and [Lck]total=6 nM.

Cellular calcium flux assays were done according to manufacturerdescriptions (Molecular Devices). In brief, actively growing RamosB-cells (ATCC) in RPM1 medium supplemented with 10% FBS (Invitrogen)were washed and re-plated in low serum medium to approximately 5×10⁵cells per 100 ul per well in 96-well plate. Compounds to be assayed weredissolved in DMSO, diluted to appropriate concentrations in low serummedium (from 0 to 10 μM final concentrations at a dilution factor of0.3), added to each well (the final DMSO concentration was 0.01% in eachwell) and incubated at 37 degree in 5% CO2 incubator for 1 hour. 100 ulcalcium assay dye (Calcium 3 assay kit, Molecular Devices) was thenadded to each well and incubated for an additional one hour. Thecompound treated cells were stimulated with a goat anti-human IgMantibody (80 ug/ml; Jackson ImmunoResearch) and read in a Flexstation11384 (Molecular Devices) at Ex=485 nm and Em=538 nm for 200 seconds.The relative fluorescence unit (RFU) and the fifty percent of inhibition(IC50%) were recorded and analyzed using a built-in SoftMax program(Molecular devices).

Data for both kinase and cellular calcium flux assays are shown in Table7. All values are shown in μM units.

TABLE 7 Assay Data for Representative Compounds Cmpd No. Btk-TRFRET (Ki)1 A 2 A 3 A 4 A 5 A 6 A 7 B 8 B 9 B 10 A 11 A 12 A 13 A 14 A 15 A 16 A17 A 18 A 19 A 20 A 21 A 22 A 23 A 24 A 26 A 27 A 28 A 29 A 30 A 31 A 32A 33 A 34 A 35 A 36 A 37 A 40 C 41 B 42 A 43 A 44 A 45 B 46 C 47 B 48 B49 B 50 B 51 B A = <100 nM; B = >100 nM and <1000 nM; C = >1000 Nm; nd =not determined

Example 12 Pharmaceutical Compositions Example 12a ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound described herein is dissolved in DMSO and then mixed with 10 mLof 0.9% sterile saline. The mixture is incorporated into a dosage unitform suitable for administration by injection.

In another embodiment, the following ingredients are mixed to form aninjectable formulation:

Ingredient Amount compound described herein 1-2 g sodium acetate buffersolution 0.4M 2.0 mL HCl (1N) or NaOH (1M) q.s. to suitable pH water(distilled, sterile) q.s. to 20 mLAll of the above ingredients, except water, are combined and heated to60-70° C. with stirring. A sufficient quantity of water at 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. to 100 g.

Example 12b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound described herein is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, the following ingredients are mixed intimatelyand pressed into single scored tablets:

Ingredient Quantity per tablet, mg compound described herein 400cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesium stearate 5

In yet another embodiment, the following ingredients are mixedintimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per tablet, mg compound described herein 200lactose, spray-dried 148 magnesium stearate 2

In some other embodiments, the following ingredients are mixed to form asuspension for oral administration:

Ingredient Amount compound described herein 1.0 g fumaric acid 0.5 gsodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 ggranulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg distilledwater q.s. to 100 mL

Example 12c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound described herein, with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 12d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound described herein is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 12e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound described herein is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing a compounddescribed herein (500 mg) with 2000 mg of Witepsol® H-15 (triglyceridesof saturated vegetable fatty acid; Riches-Nelson, Inc., New York).

Example 12f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound described herein is mixed with 1.75 g of hydroxypropylcelluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Example 12 g Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound described herein is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims. All publications,patents, and patent applications cited herein are hereby incorporated byreference for all purposes.

1.-26. (canceled)
 27. A method for treating an autoimmune disease in asubject comprising administering to a subject in need thereof aninhibitor of Bruton's tyrosine kinase (Btk).
 28. The method of claim 27,wherein the autoimmune disease is selected from systemic lupuserythematosus (SLE), rheumatoid arthritis, juvenile arthritis, psoriaticarthritis, osteoarthritis, lupus, Wegener's granulomatosis, psoriasis,Graves' disease, Sjogren's syndrome, Guillain-Barre syndrome, Addison'sdisease, or Goodpasture's syndrome.
 29. The method of claim 27, whereinthe autoimmune disease is rheumatoid arthritis.
 30. The method of claim27, wherein the autoimmune disease is systemic lupus erythematosus. 31.The method of claim 27, wherein the autoimmune disease is Wegener'sgranulomatosis.
 32. The method of claim 27, wherein the autoimmunedisease is psoriasis.
 33. A method for treating a heteroimmune conditionor disease in a subject comprising administering to a subject in needthereof an inhibitor of Bruton's tyrosine kinase (Btk).
 34. The methodof claim 33, wherein the heteroimmune condition is graft versus hostdisease.
 35. The method of claim 33, wherein the heteroimmune disease istransplantation.
 36. The method of claim 33, wherein the heteroimmunedisease is selected from allergies, allergic conjunctivitis, or allergicrhinitis.
 37. A method for treating an inflammatory disease in a subjectcomprising administering to a subject in need thereof an inhibitor ofBruton's tyrosine kinase (Btk).
 38. The method of claim 37, wherein theinflammatory disease is inflammatory bowel disease.
 39. The method ofclaim 37, wherein the inflammatory disease is asthma.
 40. The method ofany of claims 27, 33, and 37, wherein the inhibitor of Bruton's tyrosinekinase (Btk) is a reversible inhibitor of Btk.